Cp?Rh(iii) catalyzed: Ortho -halogenation of N -nitrosoanilines by solvent-controlled regioselective C-H functionalization

Article abstract of DOI:10.1039/c8ob00601f

We present a novel, efficient, and regioselective method for the rhodium-catalyzed direct C-H ortho-halogenation of anilines that involves a removable N-nitroso directing group. This method featured mild reaction conditions, wide substrate scope, good functional group tolerance and satisfactory yields. To maintain the high ortho-regioselectivity and conversion, increasing the steric hindrance of the solvent was critical. Preliminary mechanistic studies suggest that C-H activation may be involved in the rate-determining step.

Full text of DOI:10.1039/c8ob00601f

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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OrPgleanaisce&dBoionmotoaledcjuulsatr mChaermgiinstsry
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DOI: 10.1039/C8OB00601F
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ARTICLE
Cp*Rh(III) Catalyzed Ortho-Halogenation of N-Nitrosoanilines by
Solvent-Controlled Regioselective C-H Functionalization
Qiujun Peng,[a] Jian Hu,[a] Jiyou Huo,[a] Hongshun Yuan[a] and Lanting Xu,*[b] Xianhua Pan*[b]
Received 00th January 20xx,
Accepted 00th January 20xx
We present a novel, efficient, and regioselective method for the rhodium-catalyzed direct C-H ortho-halogenation of anilines
that involves a removable N-nitroso directing group. This method featured mild reaction conditions, wide substrate scope,
good functional group tolerance and satisfactory yields. To maintain the high ortho-regioselectivity and conversion,
increasing the steric hindrance of the solvent was critical. Preliminary mechanistic studies suggest that C-H activation may
be involved in the rate-determining step.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Introduction
In the last decade, substantial progress has been made in
the field of transition-metal-catalyzed C-H bond
functionalization,1 which has provided a general and efficient
method for regioselective C-X bond formation reactions.2
Despite these significant advances, the ortho-halogenation of
electron-rich anilines remains a significant challenge due to
poor ortho/para selectivity, and in most cases only para-
halogenated or over-halogenated aniline could be obtained.3-8
Among the various strategies employed to address these
challenges, the use of protecting groups on the amine
functional group has proven to be the most successful approach.
In 2006, Shi reported the first Palladium-catalyzed ortho-
halogenation of aniline by use of an acetyl protected amine as
a directing group (Scheme 1a).9 Since then, only very limited
types of protecting groups, such as sulfonyl and carbamate,
have been used similarly in the ortho C-H halogenation of
aniline (Scheme 1b-f).10-14 Other than this advancement in
aniline halogenation methods, these reactions still required
high reaction temperatures, the directing groups were not
easily removable or the substrate scope was limited to para or
meta substituted aniline.
The use of a nitroso function as a directing group was first
reported by Zhu et al., where they demonstrated successful
functionalization of the ortho C-H bond by olefination, acylation,
cyanation, acyloxylation, alkoxylation and alkynylation.15 These
previous works demonstrated that a nitroso directing group
could act as a suitable directing group since it possesses various
coordination modes to transition metal centers and is
a.School of Perfume and Aroma Technology, Shanghai Institute of Technology, 100
Haiquan Road, Shanghai, 201418, China
b.Shanghai Research Institute of Fragrance and Flavor Industry, 480 Nanning Road,
Shanghai 200232, China, E-mail: xulanting@sit.edu.cn
Scheme 1 Ortho C-H Activation/Halogenation of Aniline
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
removable. Illuminated by these findings, we envisioned that
the N-nitroso group could also be employed as a suitable
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Table 1. Reaction Optimizationa
directing group for the C(sp2)-H halogenation of anilines.16 In
this study, we report a Rh(III)-catalyzed ortho-halogenation of
anilines by using N-nitroso function as the directing group. This
reaction exhibits advantages such as high efficiency, broad
substrate scope and mild operation conditions, thus providing a
complementary protocol for the synthesis of ortho-halogenated
anilines. To our knowledge, this is the first report of the
application of an N-nitroso group as a directing group in a
regioselective C-H halogenation reaction.
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DOI: 10.1039/C8OB00601F
Results and discussion
During initial experiments and following previous work by
Glorius et al.4a, N-nitrosoanilines (1a) were reacted with
inexpensive, commercially available N-bromosuccinimide (NBS)
as the electrophilic halogen source in the presence of
[Cp*RhCl2]2, and AgSbF6, with PivOH as the additive and 1,2-
dichloroethane as the solvent. However, no desired product
was observed, and only the para-brominated product (2a) was
obtained in 36% yield which was likely via an electrophilic
substitution pathway (Table 1, Entry 1). The Nuclear Magnetic
Resonance (NMR) yield of 2a and regioselectivity remained
essentially unaffected when PivOH was not added to the
reaction. As a result, tests were performed under reaction
conditions that omitted the PivOH additive. Solvents, however,
were observed to critically influence the efficiency and
regioselectivity of the reaction. Substituting toluene and 1,4-
dioxane for the solvents instead of 1,2-dichloroethane
produced similar para-brominated products (Table 1, Entries 3-
4). However, when MeOH was used as the solvent, the target
ortho-brominated product (3a) was obtained at a 16% yield,
although this was accompanied by a 42% yield of the para-
brominated product (2a, Table 1, Entry 5). These findings
prompted our exploration of more alcoholic solvents to
determine their role in regioselectivity. We observed that
alcohol solvents with sterically more hindered OH group
produced higher ortho-regioselectivity and conversion (Table 1,
Entries 5-8). When t-BuOH was used as the solvent, total ortho-
regioselectivity was achieved and the desired product (3a)
could be produced at an 85% yield (Table 1, Entry 8). Moreover,
the best result was obtained when the reaction was performed
under air (Table 1, Entry 9). Therefor our reaction could be
operated without the protection of inert gas which simplified
the procedure. (Table 1, Entry 9).
Finally, the current optimized conditions could extend to
ortho-iodination by using N-Iodosuccinimide (NIS) as the
halogen source. Complete ortho regioselectivity was obtained
and the desired ortho-iodinated product was observed at a 96%
yield (Table 1, Entry 18). Unfortunately, this reaction failed
when N-Chlorosuccinimide was used as the chlorine source and
only starting materials were observed, even at temperatures up
to 120°C.
Once the optimized conditions were determined, we
evaluated the substrate scope and functional group tolerance
of the reaction (Table 2). We first chose substrate 1a-f, with
different N-alkyls substituted on the amino group. Benzyl
substituents and different linear-alkyl substituents on N-
nitrosoaniline like ethyl and n-propyl groups reacted well with
Further investigations revealed that an Rh(III) catalyst and
AgSbF6 were also essential for this reaction. Poor conversions
and only para-selectivity were observed when [Ru(p-
cymene)Cl2]2 and [Cp*IrCl2]2 were used as the catalyst (Table 1,
Entries 10-11). When AgSbF6 was replaced with either AgNTf2 or
AgOTf, the desired product (3a) was only obtained in 79% and
73% yields, respectively (Table 1, Entries 12-13). Control
experiments confirmed that the [Cp*RhCl2]2 catalyst and AgSbF6
counter anion were both indispensable (Table 1, Entries 14-15).
Additionally, either reducing the catalyst loading or increasing
reaction temperature resulted in poorer yields (Table 1, Entries
16-17).
NBS (3a-3d) and NIS (4a-4d) under the optimal conditions,
producing the desired products at 80-97% yields. Reactions (to
form 3a and 4a) were scaled up successfully to a 1 mmol scale.
Complete conversion was still observed for reactions, although
the yields were slightly lower. The reaction yields decreased
when substrate 1e was used and the halogenated product 3e
-
Br and 4e were only obtained at 41% and 69% yields,
-
I
respectively. No product was observed when an N-
propanenitrile substituent was employed (3f and 4f). In general,
similarly good results were achieved when the N-nitrosoaniline
starting material was substituted with electron-withdrawing or
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Table 2. Substrate Scope
ARTICLE
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DOI: 10.1039/C8OB00601F
electron-donating groups at the para position, such as methyl two ortho-halogenated regioisomers were obtained and
groups, halides, or trifluoromethyl groups (3g and 4g 4j). halogenation to the less hindered ortho-position was
Moreover, some synthetically more useful compounds were preponderant (3u 3v and 4u 4v). However, when a meta-
-
-
-
also tolerated, including N-benzyl substituted N-nitrosoanilines methyl or N-benzyl substituted substrate was used, the less
bearing phenyl, acyl, ester, nitro or benzyl alcohol groups at the hindered, ortho-position halogenated product was observed as
para-positions of the phenyl ring (4l-4p). The selectivity of a single regioisomer (3w-3x, 3zb-3zc, 4w-4y and 4za-4ze).
meta-substituted substrates was found to be controlled by Further, when substrate 1t was used, only the more sterically
steric issues from either N- or phenyl ring substituents. For hindered ortho-position halogenated regioisomer could be
example, when a meta-Cl or Br substituted substrate was used, obtained, though the yield was more moderate (3t). Some
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functional groups, especially unprotected benzyl alcohols,
carboxylic acids, nitro groups and amides could participate in
the reaction smoothly to furnish the desired products efficiently,
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DOI: 10.1039/C8OB00601F
thus offering
a convenient setup for further synthetic
transformations. Unfortunately, no product was observed
when nitrile substituent was employed, probably due to the
competitive coordination between the lone-pair electrons on
the cyano group and the Rh(III) catalyst (3k, 4k, 3z and 4z). It
must be pointed out that during the bromination process of
meta-substituted substrates, an addition of 20 mol% Zn(NTf2)2
was necessary. We speculated that Zn(NTf2)2 may have acted as
a Lewis acid and facilitated activation of the NBS, thus improving
the yield. An obvious steric hindrance effect was also observed
for the ortho-substituted N-nitrosoaniline substrates, with
markedly decreased yields under the standard reaction
Scheme 2 Preliminary Mechanistic Studies
conditions (3r-3s and 4q-4s).
To demonstrate the synthetic utility of this method, a one-
pot procedure was tested to remove the directing group under
mild conditions at 1 mmol scale. First, we have chosen 4a as
model substrate to investigate the denitrosation process of
halogenated N-nitrosamine. After exploring various reaction
conditions (see the Supporting Information for details), we were
.
pleased to find that SnCl2 2H2O/HCl system gave the best results
and obtained 6a in 81% yield. Second, a one-pot procedure was
tested to remove the directing group under mild conditions at
this same scale. When ortho-iodination reaction of substrate 4a
.
completed, SnCl2 2H2O and HCl (12 N) were subsequently added
to the solution. After 1h at 30°C, the desired denitrosation
products 6a could be isolated in 74% yield. Moreover, some
synthetically more useful compounds including 4-Cl, 3-Ac, 3-
Table 3. Removal of the NO-directing Group with One-pot
Procedure
Scheme 3 Plausible Reaction Mechanis
COOMe, 3-COOH and 3-CONH2 substituents at the phenyl ring
were tolerated (table 2) and produced moderate to good yield
(60%-84%).
Lastly, preliminary mechanistic studies were performed to
explore the Cp*Rh(III) catalyzed ortho-halogenation. No
significant H/D exchange was observed, which suggested that
the C−H activation step might be irreversible (Scheme 2a). The
kinetic isotope effect (KIE) was measured according to the
previous work (Scheme 2a),17 two parallel reactions and
intermolecular competition reaction produced KIE values of
KH/KD = 2.3 and KH/KD = 4.3, respectively. This result indicates
that the C-H bond-cleavage process is presumably the rate-
determining step.
Based on our mechanistic studies and relevant reports, a
plausible catalytic cycle was proposed shown in Scheme 3. First,
treatment of the dimeric precursor [RhCp*Cl2]2 with AgSbF6
generated the active cationic rhodium(III) species
I, which
coordinated to N-nitrosoanilines 1a and formed
(
)
intermediated II. Second, an irreversible C-H bond activation
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took place and formed the cyclic rhodium species III, which 1H × 0.11), 7.03 (dd, J = 1.3 Hz, 1H × 0.11), 4.09 (s, 3H × 0.11),
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could undergo subsequent N-Br oxidative addition to generate 3.40 (s, 3H). 13C NMR (125 MHz, CDCl3) (sDyOnIa: 1n0d.10a3n9t/iCi8soOmB0e0r6s0)1δF
Rh(V) complex IV. Lastly, a reductive elimination of the 141.70, 133.98, 133.69, 131.02, 130.74, 128.72, 128.53, 128.37,
intermediated IV liberated the final product 3a and regenerated 128.34, 120.74, 120.03, 40.05, 35.37. HRMS (ESI) m/z calculated
the Rh(III) catalyst.
for C7H8BrN2O [M+H]+, 214.9820, found 214.9820.
N-(2-Bromophenyl)-N-ethylnitrous amide (3b) Pale yellow
liquid (93% yield, 42.6 mg, syn:anti = 1:0.45). 1H NMR (500 MHz,
CDCl3) (syn and anti isomers) δ 7.76 (d, J = 7.9 Hz, 1H), 7.69 (d, J
= 8.0 Hz, 1H × 0.45), 7.47 (t, J = 7.5 Hz, 1H), 7.42-7.34 (m, 2H +
1H × 0.45), 7.29 (t, J = 7.8 Hz, 1H × 0.45), 6.99 (d, J = 7.7 Hz, 1H
× 0.45), 4.67-4.64 (m, 1H × 0.45), 4.44-4.42 (m, 1H × 0.45), 4.01
(q, J = 7.2 Hz, 2H), 1.42 (t, J = 7.2 Hz, 3H × 0.45), 1.08 (t, J = 7.2
Hz, 3H). 13C NMR (125 MHz, CDCl3) (syn and anti isomers) δ
140.20, 137.64, 133.96, 133.72, 130.90, 130.81, 129.55, 129,29,
128.40 (overlapped), 121.50, 121.40, 48.39, 41.73, 14.11, 11.14.
HRMS (ESI) m/z calculated for C8H10BrN2O [M+H]+, 228.9971,
found 228.9978.
Conclusions
In summary, we have realized a highly efficient rhodium-
catalyzed, solvent-controlled regioselective C-H halogenation of
anilines by using N-nitroso function as a suitable and removable
directing group. This reaction features good functional group
tolerance, excellent reactivity and easy operation, thus
providing a complementary protocol for synthesis of ortho-
halogenated anilines. Further efforts to explore the synthetic
application of this present regioselective halogenation reaction
are on-going in our laboratory.
N-(2-Bromophenyl)-N-propylnitrous amide (3c) Yellow
liquid (82% yield, 40.0 mg, syn:anti = 1:0.53). 1H NMR (500 MHz,
CDCl3) (syn and anti isomers) δ 7.76 (dd, J = 8.5 Hz, 0.9 Hz, 1H),
7.69 (d, J = 8.0 Hz, 1H × 0.53), 7.47 (td, J = 7.6 Hz, 0.6 Hz, 1H),
7.41-7.34 (m, 2H + 1H × 0.53), 7.29 (td, J = 8.1 Hz, 1.0 Hz, 1H ×
0.53), 6.99 (dd, J = 7.8 Hz, 0.8 Hz, 1H × 0.53), 4.59-4.54 (m, 1H ×
0.53), 4.31-4.28 (m, 1H × 0.53), 3.91 (t, J = 7.7 Hz, 2H), 1.83-1.77
(m, 2H × 0.53), 1.54-1.46 (m, 2H), 1.06 (t, J = 7.4 Hz, 3H × 0.53),
0.88 (t, J = 7.5 Hz, 3H). 13C NMR (125 MHz, CDCl3) (syn and anti
isomers) δ 140.58, 137.93, 134.01, 133.76, 130.85, 130.72,
129.38, 129.20, 128.38 (overlapped), 121.36, 121.25, 55.07,
48.20, 21.86, 19.62, 11.57, 11.24. HRMS (ESI) m/z calculated for
C9H12BrN2O [M+H]+, 243.0128, found 243.0128.
N-Benzyl-N-(2-bromophenyl)nitrous amide (3d) Yellow
liquid (89% yield, 51.8 mg, syn:anti = 1:0.44). 1H NMR (500 MHz,
CDCl3) (syn and anti isomers) δ 7.74 (dd, J = 7.4 Hz, 1.6 Hz, 1H),
7.65 (dd, J = 7.9 Hz, 1.4 Hz, 1H × 0.44), 7.34-7.29 (m, 3H + 3H ×
0.44), 7.26-7.24 (m, 2H + 2H × 0.44), 7.22-7.16 (m, 2H × 0.44),
7.12-7.08 (m, 3H), 6.50 (dd, J = 7.6 Hz, 1.6 Hz, 1H × 0.44), 6.07
(d, J = 14.5 Hz, 1H × 0.44), 5.21-5.16 (m, 2H + 1H × 0.44). 13C
NMR (125 MHz, CDCl3) (syn and anti isomers) δ 140.08, 137.32,
134.59 (overlapped), 133.89, 133.58, 130.91, 130.83, 130.02,
129.78, 129.19, 129.10, 128.85, 128.63, 128.60, 128.23, 128.07,
127.98, 121.28, 121.17, 57.20, 49.57. HRMS (ESI) m/z calculated
for C13H12BrN2O [M+H]+, 291.0127, found 291.0143.
N-(2-Bromophenyl)-N-isopropylnitrous amide (3e) Yellow
liquid (41% yield, 20.0 mg, syn:anti = 1:0.47). 1H NMR (500 MHz,
CDCl3) (syn and anti isomers) δ 7.79 (d, J = 7.9 Hz, 1H × 0.47),
7.69 (d, J = 8.0 Hz, 1H), 7.46 (t, J = 7.7 Hz, 1H × 0.47), 7.41-7.33
(m, 1H + 2H × 0.47), 7.29 (td, J = 7.9 Hz, 0.7 Hz, 1H), 6.99 (d, J =
7.8 Hz, 1H), 5.11-5.06 (m, 1H × 0.47), 4.85-4.80 (m, 1H), 1.69 (d,
J = 6.8 Hz, 6H × 0.47), 1.51 (d, J = 6.7 Hz, 3H), 1.18 (d, J = 6.7 Hz,
3H). 13C NMR (125 MHz, CDCl3) (syn and anti isomers) δ 137.70,
134.10, 133.79, 130.95, 130.80, 129.98, 129.38, 128.28, 128.07,
124.05, 122.17, 56.82, 48.05, 22.70, 21.52, 19.52. HRMS (ESI)
m/z calculated for C9H12BrN2O [M+H]+, 243.0128, found
243.0129.
Experimental
All the reactions were carried out under air atmosphere. Unless
otherwise stated, all reagents were purchased from commercial
suppliers and used without further purification. All the solvents
used for the reactions were dried according to standard
procedures. All the reactions were monitored by thin layer
chromatography (TLC, Silica gel Merck 60 F254); The spots were
visualized by UV light. Purification of products was conducted
by flash chromatography on silica gel (particle size 40-63 μm,
230-400 mesh SiliaFlash® P60 (Silicycle Inc.)). NMR spectra were
recorded on Bruker Ultrashield™ 500 MHz. Chemical shifts were
given relative to CDCl3 (7.26 ppm for 1H NMR, 77.16 ppm for 13
NMR), DMSO-d6 (2.50 ppm for 1H NMR, 39.52 ppm for 13C NMR).
High resolution ESI mass experiments were operated on a
Bruker Daltonics, Inc. APEXIII 7.0 TESLA FTMS instrument. The
starting materials N-nitrosoanilines15a,
according to the literature procedure.
C
18
were prepared
General procedure for the Cp*Rh(III) Catalyzed Ortho-
Halogenation of N-Nitrosoanilines
1a (27.2 mg, 0.2 mmol), [Cp*RhCl2]2 (6.2 mg, 5 mol %), AgSbF6
(13.8 mg, 20 mol %), and NXS (1.2 eq) were weighed into a
pressure tube, then t-BuOH (1.0 mL) was added under air. The
o
reaction mixture was stirred for 12 h at 30 C. Purification was
performed by flash column chromatography on silica gel using
n-hexane and tetrahydrofuran to afford the product 3a as a pale
yellow liquid (38.3 mg, 89%).
Characterization data for the products in Table 2
N-(2-Bromophenyl)-N-methylnitrous amide (3a). Pale
yellow liquid (89% yield, 38.3 mg). The title compound was
obtained as an inseparable mixture of syn and anti isomers, and
the syn:anti ratio was determined by 1H NMR to be
1
approximately 1: 0.11. H NMR (500 MHZ,CDCl3) (syn and anti
isomers) δ 7.75 (dd, J = 8.0 Hz, 0.8 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H
× 0.11), 7.47 (td, J = 7.8 Hz, 1.1 Hz, 1H), 7.40-7.38 (m, 1H + 1H ×
0.11), 7.36 (td, J = 7.9 Hz, 1.5 Hz, 1H), 7.29 (td, J = 8.0 Hz, 1.4 Hz,
N-(2-Bromo-4-methylphenyl)-N-methylnitrous amide (3g)
Yellow liquid (85% yield, 38.9 mg, syn:anti = 1:0.12). H NMR
(500 MHz, CDCl3) (syn and anti isomers) δ 7.55 (s, 1H), 7.49 (s,
1
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1H × 0.12), 7.28-7.24 (m, 2H), 7.20 (d, J = 7.8 Hz, 1H × 0.12), 6.90 (overlapped), 39.83, 35.20. HRMS (ESI) m/z calculated for
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+
DOI: 10.1039/C8OB00601F
(d, J = 8.0 Hz, 1H × 0.12), 4.07 (s, 3H × 0.12), 3.38 (s, 3H), 2.41 (s, C7H7BrClN2O, [M+H] , 250.9403, found 250.9412.
3H), 2.36 (s, 3H × 0.12). 13C NMR (125 MHz, CDCl3) (syn and anti
N-(2-Bromo-3-chlorophenyl)-N-methylnitrous amide (3v’)
1
isomers) δ 141.38, 139.19 (overlapped), 134.26, 134.08, 129.47, Yellow liquid (27% yield, 13.5 mg, syn:anti = 1:0.17). H NMR
129.17, 127.96, 127.82, 120.27, 119.70, 40.15, 35.45, 20.96, (500 MHz, CDCl3) (syn and anti isomers) δ 7.62 (dd, J = 8.1 Hz,
20.90. HRMS (ESI) m/z calculated for C8H10BrN2O [M+H]+, 1.3 Hz, 1H), 7.54 (dd, J = 8.1 Hz, 1.1 Hz, 1H × 0.17), 7.42 (t, J =
228.9971, found 228.9977.
8.0 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H × 0.17), 7.31 (dd, J = 7.9 Hz,
N-(2-Bromo-6-chlorophenyl)-N-methylnitrous amide (3r) 1.3 Hz, 1H), 6.94 (dd, J = 7.8 Hz, 1.2 Hz, 1H × 0.17), 4.10 (s, 3H ×
1
Yellow liquid (30% yield, 15.0 mg, syn:anti = 1:0.23). H NMR 0.17), 3.39 (s, 3H). 13C NMR (125 MHz, CDCl3) (syn and anti
(500 MHz, CDCl3) (syn and anti isomers) δ 7.68 (dd, J = 8.1 Hz, isomers) δ 143.59, 136.75, 136.65, 131.37, 131.12, 128.98,
0.9 Hz, 1H), 7.57-7.53 (m, 1H + 1H× 0.23), 7.44 (dd, J = 8.1 Hz, 128.73, 126.59, 126.46, 121.46 (overlapped), 39.85, 35.31.
0.8 Hz, 1H × 0.23), 7.32 (t, J = 8.2 Hz, 1H), 7.24 (t, J = 8.2 Hz, 1H HRMS (ESI) m/z calculated for C7H7BrClN2O [M+H]+, 250.9403,
× 0.23), 4.09 (s, 3H× 0.23), 3.33 (s, 3H). 13C NMR (125 MHz, found 250.9412.
CDCl3) (syn and anti isomers) δ 139.23, 134.49, 132.96, 132.11,
N-(2-Bromo-5-methylphenyl)-N-methylnitrous amide (3w)
131.88, 131.67, 131.61, 129.62, 129.36, 124.08, 122.31, 38.33, White solid (97% yield, 44.4 mg, syn:anti = 1:0.11). 1H NMR (500
33.85. HRMS (ESI) m/z calculated for C7H7BrClN2O [M+H]+, MHz, CDCl3) (syn and anti isomers) δ 7.59 (d, J = 8.2 Hz, 1H), 7.52
250.9403, found 250.9411.
(d, J = 8.2 Hz, 1H × 0.11), 7.20 (s, 1H), 7.16 (d, J = 8.1 Hz, 1H),
N-(1-Bromonaphthalen-2-yl)-N-methylnitrous amide (3t) 7.10 (d, J = 8.2 Hz, 1H × 0.11), 6.82 (s, 1H × 0.11), 4.07 (s, 3H ×
1
Brown liquid (51% yield, 27.0 mg, syn:anti = 1:0.15). H NMR 0.11), 3.38 (s, 3H). 2.37 (s, 3H), 2.31 (s, 3H × 0.11). 13C NMR (125
(500 MHz, CDCl3) (syn and anti isomers) δ 8.40 (d, J = 8.5 Hz, 1H), MHz, CDCl3) (syn and anti isomers) δ 141.33, 139.18, 138.99,
8.31 (d, J = 8.2 Hz, 1H × 0.15), 7.97-7.92 (m, 2H), 7.90-7.86 (m, 133.54, 133.26, 131.90, 131.54, 128.99, 128.72, 117.04, 116.36,
2H × 0.15), 7.70 (t, J = 8.2 Hz, 1H), 7.66-7.61 (m, 1H + 2H × 0.15), 40.09, 35.38, 20.79 (overlapped). HRMS (ESI) m/z calculated for
7.47 (d, J = 8.6 Hz, 1H), 7.06 (d, J = 8.6 Hz, 1H × 0.15), 4.19 (s, 3H C8H10BrN2O [M+H]+, 228.9971, found 228.9979.
× 0.15), 3.50 (s, 3H). 13C NMR (125 MHz, CDCl3) (syn and anti
N-Benzyl-N-(4-bromo-[1,1'-biphenyl]-3-yl)nitrous amide
1
isomers) δ 139.71, 134.30, 134.16, 132.62, 131.71, 129.43, (3x) Yellow liquid (92% yield, 67.4 mg, syn:anti = 1:0.42). H
129.07, 128.47 (overlapped), 128.33, 128.30, 128.13, 127.93, NMR (500 MHz, CDCl3) (syn and anti isomers) δ 7.79 (d, J = 8.3
127.84, 127.69, 124.96, 124.19, 121.53, 120.94, 39.87, 35.56. Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H × 0.42), 7.54 (dd, J = 8.3 Hz, 2.1
HRMS (ESI) m/z calculated for C11H10BrN2O [M+H]+, 264.9971, Hz, 1H), 7.43-7.42 (m, 3H + 3H × 0.42), 7.40-7.33 (m, 3H + 3H ×
found 264.9981.
0.42), 7.30-7.27 (m, 3H + 3H × 0.42), 7.25-7.23 (m, 2H × 0.42),
N-(2,5-Dibromophenyl)-N-methylnitrous amide (3u) White 7.18-7.17 (m, 2H), 6.67 (d, J = 2.0 Hz, 1H × 0.42). 6.13 (d, J = 14.4
solid (70% yield, 41.2 mg, syn:anti = 1:0.12). 1H NMR (500 MHz, Hz, 1H × 0.42), 5.26-5.22 (m, 2H + 1H × 0.42). 13C NMR (125 MHz,
CDCl3) (syn and anti isomers) δ 7.61 (d, J = 8.6 Hz, 1H), 7.56-7.52 CDCl3) (syn and anti isomers) δ 141.72, 141.52, 140.35, 138.61,
(m, 1H + 1H × 0.12), 7.49 (dd, J = 8.5 Hz, 1.9 Hz, 1H), 7.42 (dd, J 138.58, 137.67, 134.67, 134.13, 133.94, 133.76, 129.45, 129.40,
= 8.3 Hz, 1.6 Hz, 1H × 0.12), 7.17 (d, J = 1.9 Hz, 1H × 0.12), 4.09 129.32, 129.30, 129.23 (overlapped), 129.08, 128.95, 128.71,
(s, 3H × 0.12), 3.38 (s, 3H). 13C NMR (125 MHz, CDCl3) (syn and 128.57, 128.30 (overlapped), 128.11, 128.07, 126.94, 126.81,
anti isomers) δ 142.72, 135.03, 134.75, 134.06, 133.66, 131.39, 119.93 (overlapped), 57.32, 49.65. HRMS (ESI) m/z calculated
131.31, 121.70 (overlapped), 119.81, 118.73, 39.86, 35.22. for C19H16BrN2O [M+H]+, 367.0440, found 367.0460.
HRMS (ESI) m/z calculated for C7H7Br2N2O [M+H]+, 294.8899,
found 294.8914.
N-Benzyl-N-(2-bromo-5-(hydroxymethyl)phenyl)nitrous
amide (3zb) Yellow liquid (78% yield, 50.1 mg, syn:anti = 1:0.44).
N-(2,3-Dibromophenyl)-N-methylnitrous amide (3u’) 1H NMR (500 MHz, CDCl3) (syn and anti isomers) δ 7.66 (d, J =
1
Yellow liquid (20% yield, 11.8 mg, syn:anti = 1:0.15). H NMR 8.3 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H × 0.44), 7.31-7.30 (m, 1H + 1H
(500 MHz, CDCl3) (syn and anti isomers) δ 7.78-7.76 (m, 1H), × 0.44), 7.26-7.22 (m, 4H + 2H × 0.44), 7.16 (d, J = 8.1 Hz, 1H ×
7.70 (dd, J = 8.1 Hz, 1.3 Hz, 1H × 0.15), 7.35-7.34 (m, 2H), 7.30- 0.44), 7.10-7.09 (m, 2H + 2H × 0.44), 6.50 (d, J = 0.9 Hz, 1H ×
7.26 (m, 1H × 0.15), 6.97 (dd, J = 7.8 Hz, 1.3 Hz, 1H × 0.15), 4.10 0.44), 5.96 (d, J = 14.6 Hz, 1H × 0.44), 5.26 (d, J = 14.6 Hz, 1H ×
(s, 3H × 0.15), 3.38 (s, 3H). 13C NMR (125 MHz, CDCl3) (syn and 0.44), 5.13 (s, 2H), 4.54 (s, 2H), 4.40 (s, 2H × 0.44). 13C NMR (125
anti isomers) δ 143.47, 134.73, 134.52, 129.27, 129.05, 127.24, MHz, CDCl3) (syn and anti isomers) δ 141.99, 141.81, 139.98,
127.08, 126.92 (overlapped), 123.76 (overlapped), 39.83, 35.29. 137.23, 134.33, 133.82, 133.72, 133.49, 129.21, 129.20, 129.05,
HRMS (ESI) m/z calculated for C7H7Br2N2O [M+H]+, 294.8899, 128.99, 128.84, 128.63, 128.00 (overlapped), 127.90, 127.64,
found 294.8914.
119.61, 119.58, 63.51 (overlapped), 57.37, 49.84. HRMS (ESI)
N-(2-Bromo-5-chlorophenyl)-N-methylnitrous amide (3v) m/z calculated for C14H14BrN2O2 [M+H]+, 321.0233, found
White solid (59% yield, 29.4 mg, syn:anti = 1:0.12). 1H NMR (500 321.0249.
MHz, CDCl3) (syn and anti isomers) δ 7.68 (d, J = 8.6 Hz, 1H), 7.61
3-(Benzyl(nitroso)amino)-4-bromobenzoic acid (3zc) White
(d, J = 8.7 Hz, 1H × 0.12), 7.42 (d, J = 2.3 Hz, 1H), 7.36 (dd, J = 8.6 solid (37% yield, 24.8 mg, syn:anti = 1:0.60). 1H NMR (500 MHz,
Hz, 2.4 Hz, 1H), 7.29 (dd, J = 8.6 Hz, 2.4 Hz, 1H × 0.12), 7.03 (d, J DMSO-d6) (syn and anti isomers) δ 7.98 (d, J = 8.4 Hz, 1H), 7.93
= 2.4 Hz, 1H × 0.12), 4.09 (s, 3H × 0.12), 3.39 (s, 3H). 13C NMR (dd, J = 8.3 Hz, 1.7 Hz, 1H), 7.86-7.82 (m, 1H + 2H × 0.60), 7.35-
(125 MHz, CDCl3) (syn and anti isomers) δ 142.55, 134.76, 7.33 (m, 2H + 3H × 0.60), 7.29-7.23 (m, 1H + 3H × 0.60), 7.15 (d,
134.47, 134.33, 134.28, 131.16, 130.72, 128.58, 128.48, 117.94 J = 6.8 Hz, 2H), 5.94 (d, J = 14.8 Hz, 1H × 0.60), 5.55 (d, J = 14.8
6 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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Hz, 1H × 0.60), 5.18 (s, 2H). 13C NMR (125 MHz, DMSO-d6) (syn HRMS (ESI) m/z calculated for C13H12IN2O [M+HV]+ie,w3A3rti8cl.e9O9n8lin8e,
DOI: 10.1039/C8OB00601F
and anti isomers) δ 166.17, 166.07, 140.18, 137.88, 134.77, found 339.0002.
134.20, 134.01 (overlapped), 132.12, 132.04, 132.00, 131.95,
N-(2-Iodophenyl)-N-isopropylnitrous amide (4e) Yellow
130.20, 130.17, 129.68, 129.28, 129.16, 128.99, 128.91, 128.34, liquid (69% yield, 40.0 mg, syn:anti = 1:0.55). 1H NMR (500 MHz,
126.78, 126.49, 57.00, 49.91. HRMS (ESI) m/z calculated for CDCl3) (syn and anti isomers) δ 8.04 (dd, J = 7.9 Hz, 0.8 Hz, 1H ×
C14H12BrN2O3 [M+H]+, 335.0025, found 335.0046.
0.55), 7.94 (dd, J = 8.0 Hz, 0.8 Hz, 1H), 7.49 (td, J = 7.8 Hz, 1.1 Hz,
N-(2-Iodophenyl)-N-methylnitrous amide (4a) Pale yellow 1H × 0.55), 7.42 (td, J = 7.8 Hz, 1.0 Hz, 1H), 7.32 (dd, J = 7.8 Hz,
liquid (95% yield, 49.8 mg, syn:anti = 1:0.12). 1H NMR (500 MHz, 1.1 Hz, 1H × 0.55), 7.20 (td, J = 7.9 Hz, 1.3 Hz, 1H × 0.55), 7.12
CDCl3) (syn and anti isomers) δ 8.00 (d, J = 8.0 Hz, 1H), 7.91 (d, J (td, J = 7.9 Hz, 1.3 Hz, 1H), 6.93 (d, J = 7.8 Hz, 1.1 Hz, 1H), 5.07-
= 8.0 Hz, 1H × 0.12), 7.50 (td, J = 7.8 Hz, 1.2 Hz, 1H), 7.44 (t, J = 5.02 (m, 1H × 0.55), 4.75-4.70 (m, 1H), 1.77 (d, J = 6.8 Hz, 6H ×
7.8 Hz, 1H × 0.12), 7.34 (dd, J = 7.8 Hz, 1.3 Hz, 1H), 7.20 (td, J = 0.55), 1.53 (d, J = 6.7 Hz, 3H), 1.18 (d, J = 6.7 Hz, 3H). 13C NMR
7.9 Hz, 1.4 Hz, 1H), 7.12 (d, J = 7.9 Hz, 1.4 Hz, 1H × 0.12), 6.98 (125 MHz, CDCl3) (syn and anti isomers) δ 142.12, 141.97,
(d, J = 7.8 Hz, 1H × 0.12), 4.09 (s, 3H × 0.12), 3.38 (s, 3H). 13C 140.50, 140.26, 130.98, 130.74, 129.11 (overlapped), 128.98,
NMR (125 MHz, CDCl3) (syn and anti isomers) δ 145.11, 140.32, 128.94, 97.19 (overlapped), 56.91, 48.07, 22.84, 21.78, 19.67.
140.02, 131.01, 130.92, 129.66, 129.44, 127.96, 127.75, 95.43, HRMS (ESI) m/z calculated for C9H12IN2O [M+H]+, 290.9989,
95.17, 40.13, 35.54. HRMS (ESI) m/z calculated for C7H8IN2O found 290.9992.
[M+H]+, 262.9675, found 262.9688.
N-(2-Iodo-4-methylphenyl)-N-methylnitrous amide (4g)
1
N-Ethyl-N-(2-iodophenyl)nitrous amide (4b) Pale yellow Yellow liquid (82% yield, 45.3 mg, syn:anti = 1:0.12). H NMR
liquid (94% yield, 52.0 mg, syn:anti = 1:0.44). 1H NMR (500 MHz, (500 MHz, CDCl3) (syn and anti isomers) δ 7.81 (s, 1H), 7.73 (s,
CDCl3) (syn and anti isomers) δ 8.02 (dd, J = 8.0 Hz, 1.1 Hz, 1H), 1H × 0.12), 7.29 (d, J = 7.9 Hz, 1H), 7.23-7.19 (m, 1H + 1H × 0.12),
7.93 (dd, J = 8.0 Hz, 1.0 Hz, 1H × 0.44), 7.50 (td, J = 7.7 Hz, 1.2 6.84 (d, J = 8.0 Hz, 1H × 0.12), 4.07 (s, 3H × 0.12), 3.35 (s, 3H),
Hz, 1H), 7.43 (td, J = 7.6 Hz, 1.1 Hz, 1H × 0.44), 7.30 (dd, J = 7.8 2.39 (s, 3H), 2.33 (s, 3H × 0.12). 13C NMR (125 MHz, CDCl3) (syn
Hz, 1.0 Hz, 1H), 7.20 (td, J = 7.8 Hz, 1.4 Hz, 1H), 7.13 (td, J = 7.8 and anti isomers) δ 142.67, 141.46 (overlapped), 140.59,
Hz, 1.3 Hz, 1H × 0.44), 6.93 (dd, J = 7.8 Hz, 1.1 Hz, 1H × 0.44), 140.42, 130.44, 130.10, 127.47, 127.18, 95.12, 95.02, 40.23,
4.73-4.66 (m, 1H × 0.44), 4.40-4.33 (m, 1H × 0.44), 3.98 (q, J = 35.63, 20.73, 20.68. HRMS (ESI) m/z calculated for C8H10IN2O
7.3 Hz, 2H), 1.45 (t, J = 7.3 Hz, 3H × 0.44), 1.08 (t, J = 7.3 Hz, 3H). [M+H]+, 276.9832, found 276.9844.
13C NMR (125 MHz, CDCl3) (syn and anti isomers) δ 143.54,
N-(4-Chloro-2-iodophenyl)-N-methylnitrous amide (4h)
1
141.63, 140.33, 140.12, 130.93, 130.89, 129.25 (overlapped), Yellow liquid (84% yield, 49.8 mg, syn:anti = 1:0.14). H NMR
129.04, 128.96, 96.83, 96.41, 48.45, 42.01, 14.30, 11.13. HRMS (500 MHz, CDCl3) (syn and anti isomers) δ 8.00 (d, J = 1.7 Hz, 1H),
(ESI) m/z calculated for C8H10IN2O [M+H]+, 276.9832, found 7.91 (d, J = 1.6 Hz, 1H × 0.14), 7.50 (dd, J = 8.4 Hz, 1.8 Hz, 1H),
276.9846.
7.43 (dd, J = 8.4 Hz, 1.8 Hz, 1H × 0.14), 7.28 (d, J = 8.4 Hz, 1H),
N-(2-Iodophenyl)-N-propylnitrous amide (4c) Pale yellow 6.91 (d, J = 8.4 Hz, 1H × 0.14), 4.08 (s, 3H × 0.14), 3.36 (s, 3H).
liquid (80% yield, 46.5 mg, syn:anti = 1:0.50). 1H NMR (500 MHz, 13C NMR (125 MHz, CDCl3) (syn and anti isomers) δ 143.89,
CDCl3) (syn and anti isomers) δ 8.01 (d, J = 7.9 Hz, 1H), 7.93 (d, J 141.80, 139.66, 139.49, 136.04, 135.92, 129.92, 129.59, 128.43,
= 7.9 Hz, 1H × 0.50), 7.49 (t, J = 7.7 Hz, 1H), 7.42 (t, J = 7.7 Hz, 1H 128.39, 95.93, 95.49, 39.97, 35.42. HRMS (ESI) m/z calculated
× 0.50), 7.30 (dd, J = 7.7 Hz, 0.7 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H), for C7H7ClIN2O [M+H]+, 296.9286, found 296.9295.
7.12 (td, J = 7.8 Hz, 0.9 Hz, 1H × 0.50), 6.92 (d, J = 7.8 Hz, 1H ×
N-(4-Fluoro-2-iodophenyl)-N-methylnitrous amide (4i)
1
0.50), 4.62-4.57 (m, 1H × 0.50), 4.26-4.21 (m, 1H × 0.50), 3.88 (t, Yellow liquid (96% yield, 53.8 mg, syn:anti = 1:0.14). H NMR
J = 7.8 Hz, 2H), 1.88-1.75 (m, 2H × 0.50), 1.54-1.46 (m, 2H), 1.06 (500 MHz, CDCl3) (syn and anti isomers) δ 7.72 (dd, J = 7.6 Hz,
(t, J = 7.4 Hz, 3H × 0.50), 0.88 (t, J = 7.4 Hz, 3H). 13C NMR (125 2.2 Hz, 1H), 7.63 (dd, J = 7.6 Hz, 2.0 Hz, 1H × 0.14), 7.33-7.30 (m,
MHz, CDCl3) (syn and anti isomers) δ 143.91, 141.91, 140.39, 1H), 7.21 (td, J = 8.7 Hz, 2.4 Hz, 1H), 7.15 (td, J = 8.7 Hz, 2.2 Hz,
140.17, 130.85 (overlapped), 129.23, 129.21, 128.89 1H × 0.14), 6.95-6.92 (m, 1H × 0.14), 4.08 (s, 3H × 0.14), 3.35 (s,
(overlapped), 96.61, 96.22, 55.12, 48.54, 22.00, 19.59, 11.62, 3H). 13C NMR (125 MHz, CDCl3) (syn and anti isomers) δ 163.10
11.29. HRMS (ESI) m/z calculated for C9H12IN2O [M+H]+, (d, JC-F = 253.5 Hz), 163.07 (d, JC-F = 253.3 Hz), 141.73 (d, JC-F = 3.4
290.9989, found 290.9994.
Hz), 139.31 (d, JC-F = 3.8 Hz), 128.90 (d, JC-F = 8.9 Hz), 128.80 (d,
N-Benzyl-N-(2-iodophenyl)nitrous amide (4d) Yellow liquid JC-F = 9.1 Hz), 127.25 (d, JC-F = 24.7 Hz), 127.19 (d, JC-F = 24.6 Hz),
(97% yield, 65.6 mg, syn:anti = 1:0.44). 1H NMR (500 MHz, 116.96 (d, JC-F = 22.3 Hz), 116.54 (d, JC-F = 22.3 Hz), 95.55 (d, JC-F
CDCl3) (syn and anti isomers) δ 7.98 (dd, J = 8.0 Hz, 1.0 Hz, 1H), = 8.7 Hz) (overlapped), 40.12, 35.50. HRMS (ESI) m/z calculated
7.88 (dd, J = 7.9 Hz, 0.8 Hz, 1H × 0.44), 7.35-7.31 (m, 2H + 1H × for C7H7FIN2O [M+H]+, 280.9581, found 280.9593.
0.44), 7.27-7.23 (m, 3H + 2H × 0.44), 7.18 (td, J = 7.7 Hz, 1.1 Hz,
N-(2-Iodo-4-(trifluoromethyl)phenyl)-N-methylnitrous
1H × 0.44), 7.15-7.09 (m, 2H + 2H × 0.44), 7.03 (td, J = 7.9 Hz, 1.4 amide (4j) Yellow liquid (93% yield, 61.4 mg, syn:anti = 1:0.12).
Hz, 1H × 0.44), 6.99 (dd, J = 7.8 Hz, 1.3 Hz, 1H), 6.36 (dd, J = 7.8 The 13C NMR data listed here represent peak information only
1
Hz, 1.2 Hz, 1H × 0.44), 6.08 (d, J = 14.5 Hz, 1H × 0.44), 5.14-5.10 for the major syn isomer. H NMR (500 MHz, CDCl3) (syn and
(m, 2H + 1H × 0.44). 13C NMR (125 MHz, CDCl3) (syn and anti anti isomers) δ 8.25 (s, 1H), 8.15 (s, 1H × 0.12), 7.78 (d, J = 8.1
isomers) δ 143.39, 141.25, 140.28, 139.98, 134.59, 133.80, Hz, 1H), 7.71 (d, J = 8.1 Hz, 1H × 0.12), 7.46 (d, J = 8.2 Hz, 1H),
130.96, 130.93, 129.60, 129.46, 129.30, 129.05, 128.92, 128.88, 7.11 (d, J = 8.2 Hz, 1H × 0.12), 4.12 (s, 3H × 0.12), 3.40 (s, 3H).
128.66, 128.64, 128.04 (overlapped), 96.70, 96.14, 57.26, 49.91. 13C NMR (125 MHz, CDCl3) δ 148.11, 137.49 (q, JC-F = 3.7 Hz),
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132.82 (q, JC-F = 33.2 Hz), 127.97, 126.55 (q, JC-F = 3.5 Hz), 123.52 7.88 (s, 1H × 0.49), 7.33-7.24 (m, 4H + 5H × 0.49), 7.15-7.10 (m,
View Article Online
DOI: 10.1039/C8OB00601F
(q, JC-F = 271.3 Hz), 94.83, 35.30. HRMS (ESI) m/z calculated for 2H + 1H × 0.49), 6.95 (d, J = 7.9 Hz, 1H), 6.33 (d, J = 8.0 Hz, 1H ×
C8H7F3IN2O [M+H]+, 330.9549, found 330.9570.
0.49), 6.06 (d, J = 14.5 Hz, 1H × 0.49), 5.15-5.10 (m, 2H + 1H ×
N-(2-Iodo-4-nitrophenyl)-N-methylnitrous amide (4l) 0.49), 4.67 (s, 2H), 4.59 (s, 2H × 0.49). 13C NMR (125 MHz, CDCl3)
1
Yellow liquid (97% yield, 59.7 mg, syn:anti = 1:0.12). H NMR (syn and anti isomers) δ 144.27, 144.26, 142.33, 140.09, 138.19,
(500 MHz, CDCl3) (syn and anti isomers) δ 8.84 (d, J = 2.3 Hz, 1H), 137.94, 134.44, 133.70, 129.34, 129.31 (2C, overlapped),
8.73 (d, J = 2.3 Hz, 1H × 0.12), 8.37 (dd, J = 8.6 Hz, 2.4 Hz, 1H), 129.20, 128.89, 128.67 (overlapped), 128.06, 127.14, 127.08,
8.30 (dd, J = 8.6 Hz, 2.3 Hz, 1H × 0.12), 7.51 (d, J = 8.6 Hz, 1H), 96.67, 96.10, 63.47, 63.44, 57.38, 50.00. HRMS (ESI) m/z
7.17 (d, J = 8.6 Hz, 1H × 0.12), 4.14 (s, 3H × 0.12), 3.41 (s, 3H). calculated for C14H14IN2O2 [M+H]+, 369.0094, found 369.0111.
13C NMR (125 MHz, CDCl3) δ 150.23, 147.73, 135.60, 127.82,
N-(2-Fluoro-6-iodophenyl)-N-methylnitrous amide (4q)
124.46, 94.11, 35.37. HRMS (ESI) m/z calculated for C7H7IN3O3 Yellow liquid (45% yield, 25.4 mg, syn:anti = 1:0.30). The 13C
[M+H]+, 307.9527, found 307.9533.
NMR data listed here represent peak information only for the
N-Benzyl-N-(3-iodo-[1,1'-biphenyl]-4-yl)nitrous
amide major syn isomer. 1H NMR (500 MHz, CDCl3) (syn and anti
1
(4m) Yellow liquid (85% yield, 70.4 mg, syn:anti = 1:0.45). H isomers) δ 7.79 (d, J = 7.9 Hz, 1H), 7.68-7.67 (m, 1H × 0.30), 7.28-
NMR (500 MHz, CDCl3) (syn and anti isomers) δ 8.21 (d, J = 1.7 7.25 (m, 1H), 7.24-7.19 (m, 1H), 7.16-7.14 (m, 2H × 0.30), 4.09
Hz, 1H), 8.11 (d, J = 1.7 Hz, 1H × 0.45), 7.57-7.54 (m, 2H + 2H × (s, 3H × 0.30), 3.33 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 159.01
0.45), 7.50-7.34 (m, 5H + 8H × 0.45), 7.29-7.28 (m, 2H + 1H × (d, JC-F = 254.6 Hz), 135.27 (d, JC-F = 3.8 Hz), 133.57 (d, JC-F =13.6
0.45), 7.18-7.17 (m, 2H), 7.08 (d, J = 8.1 Hz, 1H), 6.46 (d, J = 8.2 Hz), 132.45 (d, JC-F =8.3 Hz), 117.00 (d, JC-F = 20.4 Hz), 98.09,
Hz, 1H × 0.45), 6.14 (d, J = 14.6 Hz, 1H × 0.45), 5.21-5.17 (m, 2H 34.45. HRMS (ESI) m/z calculated for C7H7FIN2O [M+H]+,
+ 1H × 0.45). 13C NMR (125 MHz, CDCl3) (syn and anti isomers) δ 280.9581, found 280.9594.
144.11, 144.09, 142.38, 140.14, 138.72, 138.46, 138.39, 138.28,
N-(2-Chloro-6-iodophenyl)-N-methylnitrous amide (4r)
1
134.67, 133.89, 129.50, 129.43, 129.32 (overlapped), 129.08, Yellow liquid (43% yield, 25.5 mg, syn:anti = 1:0.31). H NMR
128.99, 128.92, 128.70, 128.67, 128.47, 128.38, 128.06, 127.68, (500 MHz, CDCl3) (syn and anti isomers) δ 7.91 (d, J = 8.0 Hz, 1H),
127.65, 127.21, 127.19, 97.05, 96.56, 57.36, 49.98. HRMS (ESI) 7.79 (d, J = 8.0 Hz, 1H × 0.31), 7.57 (d, J = 8.1 Hz, 1H), 7.47 (d, J
m/z calculated for C19H16IN2O [M+H]+, 415.0301, found = 8.1 Hz, 1H × 0.31), 7.16 (t, J = 8.0 Hz, 1H), 7.07 (t, J = 8.1 Hz, 1H
415.0323.
× 0.31), 4.10 (s, 3H × 0.31), 3.32 (s, 3H). 13C NMR (125 MHz,
N-(4-Acetyl-2-iodophenyl)-N-benzylnitrous amide (4n) CDCl3) (syn and anti isomers) δ 142.34, 140.50, 138.37, 138.22,
1
Yellow liquid (78% yield, 59.3 mg, syn:anti = 1:0.45). H NMR 133.53 (overlapped), 132.06, 131.98, 130.53, 130.27, 98.84,
(500 MHz, CDCl3) (syn and anti isomers) δ 8.53 (d, J = 1.6 Hz, 1H), 96.69, 38.25, 33.89. HRMS (ESI) m/z calculated for C7H7ClIN2O
8.42 (d, J = 1.4 Hz, 1H × 0.45), 7.91 (dd, J = 8.1 Hz, 1.6 Hz, 1H), [M+H]+, 296.9286, found 296.9298.
7.75 (dd, J = 8.1 Hz, 1.5 Hz, 1H × 0.45), 7.35-7.33 (m, 1H + 1H ×
N-(5-Bromo-2-iodophenyl)-N-methylnitrous amide (4u)
0.45), 7.28-7.24 (m, 2H + 4H × 0.45), 7.10-7.08 (m, 3H), 6.48 (d, White solid (81% yield, 55.2 mg, syn:anti = 1:0.12). 1H NMR (500
J = 8.2 Hz, 1H × 0.45), 6.10 (d, J = 14.6 Hz, 1H × 0.45), 5.20 (d, J MHz, CDCl3) (syn and anti isomers) δ 7.85 (d, J = 8.5 Hz, 1H), 7.75
= 14.6 Hz, 1H × 0.45), 5.14 (s, 2H), 2.61 (s, 3H), 2.54 (s, 3H × (d, J = 8.5 Hz, 1H × 0.12), 7.49 (d, J = 2.1 Hz, 1H), 7.34 (dd, J = 8.5
0.45). 13C NMR (125 MHz, CDCl3) (syn and anti isomers) δ 195. Hz, 2.1 Hz, 1H), 7.25-7.24 (m, 1H × 0.12), 7.11 (d, J = 2.1 Hz, 1H
57, 195.51, 146.91, 145.38, 140.31, 139.77, 138.78, 138.62, × 0.12), 4.08 (s, 3H × 0.12), 3.36 (s, 3H). 13C NMR (125 MHz,
134.19, 133.44, 129.67, 129.31, 129.26, 129.21, 128.99, 128.82, CDCl3) (syn and anti isomers) δ 146.21, 141.29, 141.02, 134.15,
128.81, 128.76, 128.56, 128.22, 96.73, 96.62, 57.03, 49.50, 133.95, 131.01, 130.87, 123.01, 122.94, 93.29 (overlapped),
26.66, 26.58. HRMS (ESI) m/z calculated for C15H14IN2O2 [M+H]+, 39.95, 35.42. HRMS (ESI) m/z calculated for C7H7BrIN2O [M+H]+,
381.0094, found 381.0113.
340.8780, found 340.8795.
Methyl 4-(benzyl(nitroso)amino)-3-iodobenzoate (4o)
N-(3-Bromo-2-iodophenyl)-N-methylnitrous amide (4u’)
Yellow liquid (84% yield, 66.6 mg, syn:anti = 1:0.45). H NMR White solid (17% yield, 11.7 mg, syn:anti = 1:0.16). 1H NMR (500
(500 MHz, CDCl3) (syn and anti isomers) δ 8.63 (d, J = 1.6 Hz, 1H), MHz, CDCl3) (syn and anti isomers) δ 7.77 (d, J = 7.9 Hz, 1H), 7.68
8.52 (d, J = 1.4 Hz, 1H × 0.45), 8.00 (dd, J = 8.2 Hz, 1.7 Hz, 1H), (d, J = 8.1 Hz, 1H × 0.16), 7.38 (t, J = 7.9 Hz, 1H), 7.32 (t, J = 7.9
7.84 (dd, J = 8.2 Hz, 1.6 Hz, 1H × 0.45), 7.33-7.32 (m, 1H + 1H × Hz, 1H × 0.16), 7.26-7.24 (m, 1H), 6.89 (d, J = 7.9 Hz, 1H × 0.16),
0.45), 7.26-7.23 (m, 2H + 4H × 0.45), 7.09-7.05 (m, 3H), 6.45 (d, 4.10 (s, 3H × 0.16), 3.36 (s, 3H). 13C NMR (125 MHz, CDCl3) (syn
J = 8.2 Hz, 1H × 0.45), 6.08 (d, J = 14.6 Hz, 1H × 0.45), 5.19 (d, J and anti isomers) δ 147.28, 133.55 (overlapped), 132.11,
= 14.6 Hz, 1H × 0.45), 5.13 (s, 2H), 3.92 (s, 3H), 3.88 (s, 3H × 132.00, 130.49, 130.20, 126.45, 126.05, 104.46 (overlapped),
0.45). 13C NMR (125 MHz, CDCl3) (syn and anti isomers) δ 164.65 39.88, 35.47. HRMS (ESI) m/z calculated for C7H7BrIN2O [M+H]+,
(overlapped), 146.89, 145.36, 141.49, 140.99, 134.18, 133.43, 340.8780, found 340.8794.
1
132.39, 132.24, 130.17, 129.95, 129.42, 129.28, 129.23, 129.08,
N-(5-Chloro-2-iodophenyl)-N-methylnitrous amide (4v)
128.98, 128.81, 128.75, 128.21, 96.13, 96.07, 57.04, 52.73, White solid (67% yield, 39.7 mg, syn:anti = 1:0.12). 1H NMR (500
52.66, 49.54. HRMS (ESI) m/z calculated for C15H14IN2O3 [M+H]+, MHz, CDCl3) (syn and anti isomers) δ 7.92 (d, J = 8.5 Hz, 1H), 7.83
397.0043, found 397.0061.
(d, J = 8.5 Hz, 1H × 0.12), 7.35 (d, J = 2.2 Hz, 1H), 7.21 (dd, J = 8.5
Hz, 2.2 Hz, 1H), 7.13 (dd, J = 8.5 Hz, 2.1 Hz, 1H × 0.12), 6.98 (d, J
N-Benzyl-N-(4-(hydroxymethyl)-2-iodophenyl)nitrous
amide (4p) Yellow liquid (84% yield, 61.9 mg, syn:anti = 1:0.49). = 2.2 Hz, 1H × 0.12), 4.09 (s, 3H × 0.12), 3.36 (s, 3H). 13C NMR
1H NMR (500 MHz, CDCl3) (syn and anti isomers) δ 7.98 (s, 1H), (125 MHz, CDCl3) (syn and anti isomers) δ 146.09, 141.04,
8 | J. Name., 2012, 00, 1-3
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140.76, 135.52, 135.43, 131.23, 131.01, 128.20, 128.10, 92.96, 0.44), 6.01 (d, J = 14.6 Hz, 1H × 0.44), 5.30 (d, J = 14.6 Hz, 1H ×
View Article Online
13
DOI: 10.1039/C8OB00601F
92.35, 39.89, 35.35. HRMS (ESI) m/z calculated for C7H7ClIN2O 0.44), 5.14 (s, 2H), 3.88 (s, 3H), 3.81 (s, 3H × 0.44). C NMR (125
[M+H]+, 296.9286, found 296.9295.
MHz, CDCl3) (syn and anti isomers) δ 165.38, 165.25, 143.77,
N-(3-Chloro-2-iodophenyl)-N-methylnitrous amide (4v’) 141.71, 140.67, 140.27, 134.11, 133.34, 131.43, 131.34, 131.32,
White solid (27% yield, 16.0 mg, syn:anti = 1:0.16). The 13C NMR 131.26, 130.11, 129.85, 129.32, 129.28, 128.96, 128.78, 128.75,
data listed here represent peak information only for the major 128.20, 103.12, 103.01, 57.29, 52.60, 52.46, 49.87. HRMS (ESI)
1
syn isomer. H NMR (500 MHz, CDCl3) (syn and anti isomers) δ m/z calculated for C15H14IN2O3 [M+H]+, 397.0043, found
7.59 (dd, J = 8.1 Hz, 1.1 Hz, 1H), 7.50 (dd, J = 8.1 Hz, 1.2 Hz, 1H × 397.0058.
0.16), 7.45 (t, J = 7.9 Hz, 1H), 7.38 (t, J = 7.9 Hz, 1H × 0.16), 7.22
N-Benzyl-N-(5-(hydroxymethyl)-2-iodophenyl)nitrous
(dd, J = 7.8 Hz, 1.1 Hz, 1H), 6.85 (dd, J = 7.8 Hz, 1.1 Hz, 1H × 0.16), amide (4zb) Yellow liquid (94% yield, 69.2 mg, syn:anti = 1:0.44).
4.11 (s, 3H × 0.16), 3.37 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 1H NMR (500 MHz, CDCl3) (syn and anti isomers) δ 7.91 (d, J =
147.32, 140.81, 130.10, 129.98, 125.98, 101.31, 35.48. HRMS 8.2 Hz, 1H), 7.81 (d, J = 8.2 Hz, 1H × 0.44), 7.32-7.31 (m, 1H + 1H
(ESI) m/z calculated for C7H7ClIN2O [M+H]+, 296.9286, found × 0.44), 7.26-7.23 (m, 3H + 2H × 0.44), 7.12-7.09 (m, 2H + 2H ×
296.9296.
0.44), 7.01 (br, 1H + 1H × 0.44), 6.38 (s, 1H × 0.44), 6.00 (d, J =
N-(2-Iodo-5-methylphenyl)-N-methylnitrous amide (4w) 14.5 Hz, 1H × 0.44), 5.20 (d, J = 14.6 Hz, 1H × 0.44), 5.10 (s, 2H),
White solid (98% yield, 54.1 mg, syn:anti = 1:0.11). 1H NMR (500 4.54 (s, 2H), 4.39 (s, 2H × 0.44). 13C NMR (125 MHz, CDCl3) (syn
MHz, CDCl3) (syn and anti isomers) δ 7.84 (d, J = 8.1 Hz, 1H), 7.76 and anti isomers) δ 143.40, 142.88, 142.71, 141.30, 140.23,
(d, J = 8.1 Hz, 1H × 0.11), 7.15 (s, 1H), 7.02 (d, J = 8.1 Hz, 1H), 139.93, 134.36, 133.63, 129.35, 129.28, 129.25, 129.16, 128.87,
6.95 (d, J = 8.1 Hz, 1H × 0.11), 6.78 (s, 1H × 0.11), 4.07 (s, 3H × 128.69, 128.65, 128.06, 127.53, 127.41, 94.67, 94.23, 63.59
0.11), 3.36 (s, 3H), 2.37 (s, 3H), 2.31 (s, 3H × 0.11). 13C NMR (125 (overlapped), 57.43, 50.16. HRMS (ESI) m/z calculated for
MHz, CDCl3) (syn and anti isomers) δ144.89, 140.21, 139.98, C14H14IN2O2 [M+H]+, 369.0094, found 369.0108.
139.90, 139.62, 132.04, 131.87, 128.75, 128.30, 90.98, 90.75,
40.14, 35.54, 27.65, 20.82. HRMS (ESI) m/z calculated for solid (93% yield, 71.1 mg, syn:anti = 1:0.54). 1H NMR (500 MHz,
C8H10IN2O [M+H]+, 276.9832, found 276.9845.
DMSO-d6) (syn and anti isomers) δ 13.26 (br, 1H), 8.19 (d, J = 8.1
3-(Benzyl(nitroso)amino)-4-iodobenzoic acid (4zc) White
N-Benzyl-N-(4-iodo-[1,1'-biphenyl]-3-yl)nitrous amide (4x) Hz, 1H), 8.07 (d, J = 8.2 Hz, 1H × 0.54), 7.74-7.71 (m, 2H), 7.64
1
Yellow liquid (94% yield, 77.9 mg, syn:anti = 1:0.42). H NMR (dd, J = 8.2 Hz, 1.6 Hz, 1H × 0.54), 7.35-7.34 (m, 2H + 1H × 0.54),
(500 MHz, CDCl3) (syn and anti isomers) δ 8.04 (d, J = 8.3 Hz, 1H), 7.30-7.23 (m, 1H + 4H × 0.54), 7.15-7.14 (m, 2H), 7.12 (d, J = 1.5
7.94 (d, J = 8.3 Hz, 1H × 0.42), 7.42-7.34 (m, 6H + 8H × 0.42), Hz, 1H × 0.54), 5.99 (d, J = 14.7 Hz, 1H × 0.54), 5.43 (d, J = 14.7
7.30-7.28 (m, 3H + 1H × 0.42), 7.21-7.18 (m, 3H + 2H × 0.42), Hz, 1H × 0.54), 5.16 (s, 2H). 13C NMR (125 MHz, DMSO-d6) (syn
6.55 (d, J = 2.0 Hz, 1H × 0.42), 6.16 (d, J = 14.5 Hz, 1H × 0.42), and anti isomers) δ 166.41, 166.29, 143.72, 142.05, 141.12,
5.21-5.19 (m, 2H + 1H × 0.42). 13C NMR (125 MHz, CDCl3) (syn 140.62, 134.82, 133.95, 132.46, 132.33, 131.70 (overlapped),
and anti isomers) δ 143.76, 142.53, 142.35, 141.73, 140.51, 129.77, 129.61, 129.45, 129.28, 129.18, 128.99, 128.92, 128.35,
140.15, 138.62, 138.60, 134.71, 133.88, 129.52, 129.48, 129.46 104.63, 104.53, 57.07, 50.10. HRMS (ESI) m/z calculated for
(overlapped), 129.08, 128.98, 128.94, 128.73, 128.33, 128.22, C14H12IN2O3 [M+H]+, 382.9887, found 382.9912.
128.14 (overlapped), 128.09 (overlapped), 126.89, 126.75,
94.94, 94.46, 57.36, 49.95. HRMS (ESI) m/z calculated for solid (86% yield, 65.6 mg, syn:anti = 1:0.47). 1H NMR (500 MHz,
C19H16IN2O [M+H]+, 415.0301, found 415.0320.
DMSO-d6) (syn and anti isomers) δ 8.15-8.13 (m, 2H), 8.02-8.00
3-(Benzyl(nitroso)amino)-4-iodobenzamide (4zd) White
N-(5-Acetyl-2-iodophenyl)-N-benzylnitrous amide (4y) (m, 2H × 0.47), 7.82 (d, J = 1.7, 1H), 7.72 (dd, J = 8.1 Hz, 1.4 Hz,
1
Yellow liquid (85% yield, 64.6 mg, syn:anti = 1:0.52). H NMR 1H), 7.62 (dd, J = 8.1 Hz, 1.3 Hz, 1H × 0.47), 7.57 (br, 1H), 7.48
(500 MHz, CDCl3) (syn and anti isomers) δ 8.11 (d, J = 8.2 Hz, 1H), (br, 1H × 0.47), 7.33 (br, 2H + 1H × 0.47), 7.29-7.24 (m, 1H + 5H
8.01 (d, J = 8.3 Hz, 1H × 0.52), 7.69 (dd, J = 8.2 Hz, 1.4 Hz, 1H), × 0.47), 7.16-7.15 (m, 2H), 5.90 (d, J = 14.7 Hz, 1H × 0.47), 5.53
7.61 (dd, J = 8.3 Hz, 1.4 Hz, 1H × 0.52), 7.47 (d, J = 1.4 Hz, 1H), (d, J = 14.7 Hz, 1H × 0.47), 5.17 (s, 2H). 13C NMR (125 MHz,
7.36-7.35 (m, 1H + 1H × 0.52), 7.29-7.26 (m, 2H +4H × 0.52), DMSO-d6) (syn and anti isomers) δ 166.59, 166.52, 143.53,
7.12-7.11 (m, 2H), 6.82 (d, J = 1.4 Hz, 1H × 0.52), 6.12 (d, J = 14.5 141.85, 140.65, 140.05, 135.80, 135.71, 134.74, 133.92, 130.12,
Hz, 1H × 0.52), 5.19-5.14 (m, 2H + 1H × 0.52), 2.44 (s, 3H), 2.28 130.01, 129.82, 129.42, 129.11, 128.94, 128.86, 128.29, 128.22,
(s, 3H × 0.52). 13C NMR (125 MHz, CDCl3) (syn and anti isomers) 127.88, 102.18, 102.07, 57.17, 50.18. HRMS (ESI) m/z calculated
δ 195.91, 143.79, 141.75, 140.79, 140.41, 137.81, 137.68, for C14H13IN3O2 [M+H]+, 382.0046, found 382.0062.
134.27, 133.47, 129.82, 129.81, 129.41, 129.37, 129.08, 129.00,
128.88, 128.82, 128.77, 128.28, 103.40, 103.15, 57.22, 49.61, Yellow liquid (85% yield, 62.3 mg, syn:anti = 1:0.40). H NMR
26.40, 26.18. HRMS (ESI) m/z calculated for C15H14IN2O2 [M+H]+, (500 MHz, CDCl3) (syn and anti isomers) δ 7.87 (d, J = 8.1 Hz, 1H),
N-Benzyl-N-(5-ethyl-2-iodophenyl)nitrous amide (4ze)
1
381.0094, found 381.0106.
7.77 (d, J = 8.1 Hz, 1H × 0.40), 7.34-7.33 (m, 1H + 1H × 0.40),
Methyl 3-(benzyl(nitroso)amino)-4-iodobenzoate (4za) 7.28-7.25 (m, 2H + 4H × 0.40), 7.13-7.12 (m, 2H), 7.00 (d, J = 8.0
1
Yellow liquid (85% yield, 67.4 mg, syn:anti = 1:0.44). H NMR Hz, 1H), 6.90 (d, J = 8.0 Hz, 1H × 0.40), 6.81 (s, 1H), 6.15 (s, 1H ×
(500 MHz, CDCl3) (syn and anti isomers) δ 8.08 (dd, J = 8.2 Hz, 0.40), 6.09 (d, J = 14.4 Hz, 1H × 0.40), 5.12-5.10 (m, 2H + 1H ×
1.5 Hz, 1H), 7.97 (dd, J = 8.2 Hz, 1.5 Hz, 1H × 0.44), 7.77 (d, J = 0.40), 2.55 (q, J = 7.6 Hz, 2H), 2.41 (q, J = 7.6 Hz, 2H × 0.40 ), 1.12
8.3 Hz, 1H), 7.68-7.67 (m, 1H + 1H × 0.44), 7.34 (br, 1H + 1H × (t, J = 7.5 Hz, 3H), 0.98 (t, J = 7.4 Hz, 3H × 0.40). 13C NMR (125
0.44), 7.29-7.25 (m, 2H + 4H × 0.44), 7.12-7.09 (m, 2H +1H × MHz, CDCl3) (syn and anti isomers) δ 145.84, 145.59, 143.19,
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136, 17722; (b) A. B. Pawar and D. M. Lade, VOiewrgA.rtiBclieoOmnloinle.
Chem., 2016, 14, 3275.
141.15, 139.89, 139.56, 134.67, 133.89, 130.77, 130.75, 129.44,
129.41, 129.32, 128.98, 128.80, 128.58, 127.99 (overlapped),
92.55, 91.93, 57.33, 49.92, 28.06, 27.96, 15.08, 14.83. HRMS
(ESI) m/z calculated for C15H16IN2O [M+H]+,367.0301, found
367.0320.
8
9
For selected examples of Cu-catalyzedDdOirI:e1c0t.1e0d39h/aCl8oOgeBn00a6ti0o1nF
of C-H bonds, see: (a) X. Chen, X.-S. Hao, C. E. Goodhue and J.-
Q. Yu, J. Am. Chem. Soc., 2006, 128, 6790; (b) S. Mo, Y. Zhu
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Liu and B.-F. Shi, Chem. Commun., 2015, 51, 5093; (d) W. C.
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X. Wan, Z. Ma, B. Li, K. Zhang, S. Cao, S. Zhang and Z.-J. Shi, J.
Am. Chem. Soc., 2006, 128, 7416-7417.
Conflicts of interest
There are no conflicts of interest to declare.
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Acknowledgements
This work was supported by Shanghai Sailing Program
(17YF1418900).
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,
10 | J. Name., 2012, 00, 1-3
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