A Metal-Free Direct Arene C?H Amination

Article abstract of DOI:10.1002/adsc.202100236

The synthesis of aryl amines via the formation of a C?N bond is an essential tool for the preparation of functional materials, active pharmaceutical ingredients and bioactive products. Usually, this chemical connection is only possible by transition metal-catalyzed reactions, photochemistry or electrochemistry. Here, we report a metal-free arene C?H amination using hydroxylamine derivatives under benign conditions. A charge transfer interaction between the aminating reagents TsONHR and the arene substrates enables the chemoselective amination of the arene, even in the presence of various functional groups. Oxygen was crucial for an effective conversion and its accelerating role for the electron transfer step was proven experimentally. In addition, this was rationalized by a theoretical study which indicated the involvement of a dioxygen-bridged complex with a “Sandwich-like” arrangement of the aromatic starting materials and the aminating agents at the dioxygen molecule. (Figure presented.).

Full text of DOI:10.1002/adsc.202100236

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DOI: 10.1002/adsc.202100236
A Metal-Free Direct Arene CÀ H Amination
Tao Wang,a Marvin Hoffmann,b Andreas Dreuw,b Edina Hasagić,c Chao Hu,a
Philipp M. Stein,a Sina Witzel,a Hongwei Shi,a Yangyang Yang,a
Matthias Rudolph,a Fabian Stuck,a Frank Rominger,a Marion Kerscher,d
Peter Comba,d and A. Stephen K. Hashmia, e,*
a
Organisch-Chemisches Institut, Heidelberg University, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
E-mail: hashmi@hashmi.de
b
Interdisciplinary Center for Scientific Computing, Heidelberg University, Im Neuenheimer Feld 205 A, D-69120 Heidelberg,
Germany
c
Chemistry Department, Faculty of Natural Science, Sarajevo University, Zmaja od Bosne 33-35, 71000 Sarajevo, Bosnia and
Herzegovina
d
Anorganisch-Chemisches Institut, Heidelberg University, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
Chemistry Department, Faculty of Science, King Abdulaziz University (KAU), Jeddah 21589, Saudi Arabia
e
Manuscript received: February 22, 2021; Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100236
© 2021 The Authors. Advanced Synthesis & Catalysis published by Wiley-VCH GmbH. This is an open access article under the
terms of the Creative Commons Attribution Non-Commercial NoDerivs License, which permits use and distribution in any
medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Abstract: The synthesis of aryl amines via the formation of a CÀ N bond is an essential tool for the preparation
of functional materials, active pharmaceutical ingredients and bioactive products. Usually, this chemical
connection is only possible by transition metal-catalyzed reactions, photochemistry or electrochemistry. Here,
we report a metal-free arene CÀ H amination using hydroxylamine derivatives under benign conditions. A
charge transfer interaction between the aminating reagents TsONHR and the arene substrates enables the
chemoselective amination of the arene, even in the presence of various functional groups. Oxygen was crucial
for an effective conversion and its accelerating role for the electron transfer step was proven experimentally. In
addition, this was rationalized by a theoretical study which indicated the involvement of a dioxygen-bridged
complex with a “Sandwich-like” arrangement of the aromatic starting materials and the aminating agents at the
dioxygen molecule.
Keywords: metal-free; direct amination; mild condition; charge transfer; oxygen-accelerated
Introduction
the Chan-Lam reaction[5]) become extremely popular
even in industry. However, functionalized arene sub-
The past decades have witnessed a significant im- strates (such as aryl halides, aryl boronic acids or other
provement of amination reactions of arenes. This was aryl transfer reagents) are needed, accompanied by
driven by the importance of aryl amines as key units in extra steps for the installation onto simple arenes.[6] As
pharmaceuticals, agrochemicals, organic materials, and such, methods for the direct amination of unfunctional-
in natural bioactive products.[1] The traditional method ized arenes are highly desirable while far from being
for the introduction of an amino group on arenes is a developed.[7]
sequence composed of nitration followed by reduction
A powerful route to aryl amines is the direct arene
and often further manipulations. This route needs harsh CÀ H amination through photochemistry[8] (Scheme 1a,
conditions and often is accompanied by poor left), electrochemistry[9] (Scheme 1a, left) and transi-
selectivity.[2] As an alternative strategy, transition tion metal-catalyzed amination[10] (Scheme 1a, right).
metal-catalyzed coupling reactions (such as the Ull- Among these, simple hydroxylamine or its derivatives
mann reaction,[3] the Buchwald-Hartwig reaction[4] or are often used for the construction of CÀ N bonds. For
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CÀ H amination of arenes under benign conditions, is
still of high importance. In principle, metal-free
processes are preferred, especially in the pharmaceut-
ical industry, where the removal of undesired metal
contamination is costly and the use of any metal in the
last steps of a drug synthesis needs to be avoided.
Herein, we report that charge transfer in the transition
state and radical recombination can lead to para-
selective amination products without metal and under
mild conditions in good yields (especially for electron-
rich substrates) (Scheme 1b).
Scheme 1. Methods for the Synthesis of Aryl Amines.
example, in 2014, Sanford[8a] reported a new photo-
catalytic, Ir(ppy)3-catalyzed method with N-acyloxyph-
Results and Discussion
thalimides for the CÀ H amination of arenes and Inspired by Falck[10b] and He,[13] we initially planned to
heteroarenes; and also Baran[10a] developed an iron- conduct arene CÀ H aminations with gold nitrene
catalyzed arene CÀ H amination with NSP (N-succini- species derived from TsONHBoc (1). TsONHBoc,
midyl perester) as reagent in the same year. Later in similar to MsOOMs[14] (reported by Ritter, who
2016, Falck[10b] invented a rhodium-catalyzed directed implemented a metal-free arene CÀ H oxygenation in
arene CÀ H amination with TsONHMe under mild HFIP), was supposed to react with arenes to give
conditions, while only electron-rich substrates were useful and challenging anilines. The CÀ H amination
tolerated. Later, a direct arene CÀ H amination was product, the aniline 2, was obtained in moderate yield
successful by using hydroxylamine derivatives when mesitylene was treated with 1 and a catalytic
(MsONH2 ·HOTf, RCO2NH2 ·HOTf) in combination amount of AuCl3 in TFE at room temperature. After a
with iron by Morandi,[10c] Ning[10d] and Ritter.[10e] In systematic investigation using mesitylene as arene
2017, ArONRR’ as aminating reagents were developed (Table 1), we found that the reaction was highly
by Leonori[8e] in a Ru(bpy3)Cl2-catalyzed arene CÀ H solvent-dependent. No desired product was observed
amination. Togni and Carreira[8h] as well as Ritter[8g] with a nonpolar solvent. TFE as polar solvent gave a
reported that N-OTf pyridine as pyridine radical cation moderate yield (41%) while the strongly polar, non-
could be used for the construction of CÀ N bonds in nucleophilic and strong hydrogen-bond donating HFIP
2019. Recently, in an iron-catalyzed process, meta-
CÀ H aminated products were achieved with HOSA
directing group by Falck;[10f] and a Ti-catalyzed arene
(hydroxylamine-O-sulfonic acid) and picolinates as
Table 1. Optimization of the CÀ H Amination of Mesitylene
with TsONHBoc.
CÀ H amination was reported with simple NH2OH·HCl
by Sanford.[10g] Besides, commercially available HOSA
and DPH (O-(2,4-dinitrophenyl)hydroxylamine) were
used for aziridinations of olefins with rhodium as
catalyst, which was reported by Kürti and Falck.[11] For
entry
solvent
additive
yield[a]
these protocols metals are needed, which leads to
economic pressure in the purification step (removal of
the metal contamination), especially in pharmaceutical
industry, special equipment, and often expensive
catalysts are necessary for the methods mentioned
above. Besides, several publications on intramolecular
arene CÀ H amination in a metal-free condition with
aryl or indolyl hydroxylamine derivatives were
achieved by Bower,[12] affording the product of the
dearomatization of arene and indole. Additionally,
Ritter[10e] was the first to report that a derivative of
hydroxylamine (MsONH2 ·HOTf) could achieve an
arene CÀ H amination under metal-free conditions with
the restriction that only electron-deficient arenes could
be applied (Scheme 1a, right). He documented this by
the conversion of three substrates.[10e]
1
2
3
4
5
6
DCM (0.1 M, r.t.)
TFE (0.1 M, r.t.)
TFE (0.1 M, r.t.)
HFIP (0.1 M, r.t.)
HFIP (0.2 M, r.t.)
HFIP (0.4 M, r.t.)
AuCl3
AuCl3
none
none
none
none
none
none
none
0
41%
45%
67%
70%
76%
70%
°
7
HFIP (0.4 M, 50 C)
8[b]
9[d]
HFIP (0.4 M, r.t.)
HFIP (0.4 M, r.t.)
81% (81%[c])
74%
Reaction conditions: mesitylene (0.2 mmol), TsONHBoc
(0.3 mmol), AuCl3 (0.01 mmol), HFIP (0.5 mL), 36 h.
[a] NMR yield (1,3,5-trimethoxybenzene as internal standard).
[b] mesitylene (0.2 mmol), TsONHBoc (0.4 mmol), HFIP
(0.5 mL), 36 h.
[c] isolated yield.
[d] mesitylene (0.2 mmol), MsONHBoc (0.4 mmol), HFIP
(0.5 mL), 36 h.
Despite the significant advances, a direct CÀ N bond
formation, particularly a method that enables a direct
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provided a good yield (67%). Surprisingly, a better with Falck’s methodology[10b] (Boc-MSH, TFA,
yield was obtained in the absence of a gold catalyst. Rh2(esp)2 in TFE at room temperature), however,
Furthermore, concentration also effected this reaction; anisole could not be totally converted to aniline even
a higher yield (81%) was obtained at higher concen- after 2 days. Instead, 1 provided good yields with a
trations. Room temperature was superior to elevated rhodium catalyst in HFIP. But benzene (11) or
temperatures and the yield was slightly increased when heteroarenes (dibenzothiophene 13, pyridine 14) gave
mesitylene was treated with 2 equivalents of 1. A poor yields or no desired aminated products.
control experiment with only 1 in HFIP showed that in
The successful arene CÀ H amination towards
this slightly acidic solvent the Boc group is cleaved off primary amines inspired us to explore a new method to
within 3 h (Figure S1–S2). MsONHBoc, which would construct secondary aryl amines under metal-free and
generate less by-product, could also afford desired mild conditions (Table 3). N,2,4,6-tetramethylaniline
aminating product, but in lower yield (74%) than 1.
was afforded in moderate yield (50%) when mesitylene
Under the optimized conditions we explored the was treated with in situ-generated TsONHMe (16) in
scope with respect to the arenes, using 1 as the HFIP in the presence of TFA (entry 1). The reaction
aminating reagent (Table 2). Trisubstituted symmetric with pre-prepared 16 provided a better yield (83%) of
benzenes provided moderate to good yields (2, 4–5), the amine product (entry 2). TsOH as additive slightly
however, tetra- and pentasubstituted benzenes only decreased the yield (entry 3), while K2CO3 almost
gave poor yields (6, 7). While sterically being not totally inhibited the reaction (entry 4). This behavior
more hindered than 2, 4–5, the very electron-rich seems to indicate that a mild acidic character is needed,
anilines 6 and 7 are very sensitive towards electro- but with increasing acid strength reagent 16 is
philes and oxidants. However, the more powerful protonated, which lowers the reactivity. Ambient light
aminating reagent MsONH2 ·HOTf (3), could success- had no effect (entry 5), the conversion was as efficient
fully implement electron-deficient arenes (8–10) ami- as the reaction in the dark. Oxygen indeed played an
nated with good yields at higher temperature, but poor important role in our system (entry 7) and the yield
on electron-neutral (11) and no aminated product on was significantly decreased under argon atmosphere
electron-rich arenes (12), which is consistent with (entry 6, also compare the discussion below).
Ritter’s report.[10e] Electronically neutral arenes and MsONHMe as aminating reagent would generate less
electron-rich anisoles for yet unknown reasons did not by-product, but it gave a lower yield (entry 8, 76%)
react with 1 or 3, even under prolonged reaction time compared to 16. Two equivalents of 16 without any
and at elevated temperature. Anisole could be aminated additives in HFIP as solvent turned out to be optimal
Table 2. Substrate Scope with Respect to the Arenes for the
Table 3. Optimization of the CÀ H Amination between Mesity-
Synthesis of Primary Aryl Amines.
lene and TsONHMe.
entry
R
additive
Yield[a]
1
2
3
4
Boc
H
H
H
H
H
H
H
2 eqs TFA
none
1 eq TsOH·H2O
1 eq K2CO3
none
none
none
none
50%
83% (83%)[b]
76%
trace
80%
74%
81%
5[c]
6[d]
7[e]
8[f]
76%
Reaction conditions:
[a] arene (0.2 mmol), TsONHBoc (0.4 mmol), HFIP (0.5 mL), r.
t., 36 h–10 d, isolated yield, Isomeric ratio (A:B:C) deter-
Reaction conditions: Mesitylene (0.2 mmol), aminating reagent
(0.4 mmol), HFIP (0.5 mL), 36 h.
mined by isolated isomers;
arene (0.2 mmol), MsONH2 ·HOTf (0.4 mmol), 60 C or
[a] NMR yield (1,3,5-trimethoxybenzene as internal standard).
[b] isolated yield.
[b]
°
80 C, 12 h–36 h, isolated yield;
[c] in the dark.
°
[c] Isomeric ratio (A:B) determined by NMR;
[d] under argon atmosphere.
[d] arene (0.2 mmol), Rh2(esp)2 (0.004 mmol), TsONHBoc
(0.4 mmol), HFIP (0.5 mL), r.t. 12 h, Isomeric ratio (A:B:
C) determined by isolated isomers.
[e] under oxygen atmosphere
[f] mesitylene (0.2 mmol), MsONHMe (0.4 mmol) instead of
TsONHMe, HFIP (0.5 mL), 36 h.
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for the synthesis of secondary aryl amines. All were introduced on 1,3-dimethoxybenzene derivatives
reactions were performed in new reaction vials and (63–68), such as ester, aminoacyl, cyano, nitro, OTs,
ICP measurements of metal concentrations confirmed OMs and OTf. The reaction was also amenable to
that trace metals are not involved in the CÀ N bond install a methylamine group on a range of substituted
formation (Table S1). Despite mesitylene’s weak ben- naphthalenes (69–72) and fluorenes (73, 74). Hetero-
zylic CÀ H bonds, which are prone to benzylic CÀ H arenes, dibenzofuran (75) and N-tosylcarbazole (76),
aminations, only an aromatic Csp2À H amination was gave high to excellent yields and very good selectivity.
observed in excellent chemoselectivity. No double Biphenyl substrates (77–80) were also tolerated in our
aminations were observed with our system.
system in good to excellent yield, especially for 4-
Next, we explored the scope with respect to the methyl-1,1’-biphenyl (77), which afforded the sole
arenes in combination with 16. As shown in Table 4, isomer. Electronically neutral and electron-deficient
for simple mono-alkylsubstituted benzenes, only the arenes (81–83) could not provide the desired anilines;
corresponding para-substituted aniline derivatives electron-rich heteroarenes (84, 85) afforded traces of
were generated, albeit in low to moderate yields (17– anilines; aldehyde, boronic ester and alkyne (86–88)
20). Dialkyl-substituted benzene derivatives delivered were not tolerated in our conditions. Methyl benzoate
good to excellent yields as well as good selectivity 82 also failed. Compared to Falck’s work[10b] (Rh-
(21–26). With p-cymene (21), m-xylene (23), 1,3- catalyzed arene CÀ H amination, also with TsONHMe),
diethylbenzene (25) and 1,3-disopropylbenzene (26), our protocol shows a broader substrate scope albeit
only one isomer was obtained; only in the case of o- with prolonged reaction time, especially mono-substi-
xylene (22), ortho-substitution took place as a side tuted arenes, heterocycles, heteroarenes and biphenyls
reaction. Indan (27) and tetralin (28) reacted as well, are exclusively mentioned in this study (Table 5).
but in line with the results for o-xylene with poor
To further demonstrate the scope of the amination
selectivity. Heterocycles (29–31) also achieved a good reagents, we investigated the protocol with mesitylene
yield, and only one isomer was afforded for 1- as a model arene (Table 6). An electron-rich amination
tosylindoline (30). Trialkylsubstituted and polyalkyl- reagent showed a better yield compared to electron-
substituted benzene derivatives (15, 32–36) proceeded neutral or electron-poor ones (94–98). Products (94)
efficiently with high yields. Besides, electron-rich and (96) were formed in low yields with the sensitive
anisoles and their derivatives also performed smoothly 89 or the branched aminating reagent 91, and sterically
in our system. The successful synthesis of the para- hindered reagent (99) also worked. Remarkably,
isomer of (4-bromobutoxy)benzene (38) was especially propargyl amine (104) still could be isolated in 35%
°
noteworthy, as it turned out to be unstable above 35 C. yield. No product could be assessed from N-benzyl-O-
Exclusively the para-isomer was obtained for 1- tosylhydroxylamine (105) and a tertiary aryl amine
bromo-4-phenoxybenzene (39), albeit in moderate was only obtained in low yield (106).
yield, in contrast to diphenylether (40). 2-Meth-
To evaluate whether this methodology could be
ylanisole (41) delivered only one isomer compared to applied to functionalizations and late-stage functional-
3-methylanisole (42). The yields were increased with izations, respective drugs and derivatives of natural
the steric hindrance for 4-substituted anisoles (43–46) bioactive molecules were subjected to our protocol
as self-coupling of the amination products were (Table 7). 7-Methoxycourmarin (107) (fragrance), 1-
inhibited (also see the discussion below). 1-Allyl-4- methoxy-4-(trifluoromethoxy) benzene (108) (precur-
methoxybenzene (47), with an olefin, which possibly sor for delamanid) and 4-methoxy-1,1’-biphenyl (109)
is sensitive to aziridination with hydroxylamine deriv- (precursor for bifenazate), all delivered the amination
ative 16, was converted smoothly in moderate yield products in moderate to excellent yields. In addition,
(no other products could be isolated).
natural bioactive products, such as derivatives of L-
Aryl halides had to be reacted longer to finish the tyrosine and estrone (110, 111), were tested under
reaction smoothly by adding 4 equivalents of 16. As standard conditions, delivering excellent to moderate
the halogen was untouched, the products are precursors yields, respectively. Various pharmaceuticals including
for further manipulation (48–53). Poly-substituted naproxen, etofenprox, gemfibrozil, guaifenesin, indo-
anisole derivatives (54–57) reacted readily with good methacin, and metaxalone (112–117) were also ami-
yields and, except for 54, in good selectivity. Different nated to give the products. Metoprolol (118, a top 150
from o-xylene, 1,2-dimethoxybenzene (58) only pro- best seller in 2018) and empaglifiozin (119, a top 50
duced one isomer in excellent yield; but 1,3-dimeth- best seller in 2018) underwent functionalization
oxybenzene (59) and 1,4-dimethoxybenzene (60) de- smoothly in moderate yield. Besides, to demonstrate
livered similar results compared to p-xylene and m- the utility of 16 as a potential direct amination reagent,
xylene, respectively. Electron-rich 1,3,5-trimeth- a large-scale (1 g) reaction was successfully carried out
oxybenzene (61) was also aminated in good yield. almost without any loss compared to the smaller scale
Fortunately, high to excellent yields, except for 62, when 2,6-dimethoxyphenyl 4-methylbenzenesulfonate
were obtained even if electron-withdrawing groups was used as substrate (Scheme 2 and Scheme S1).
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Table 4. Scope of Arenes for the Synthesis of Secondary Aryl Amines.
Reaction conditions: arene (0.2 mmol), TsONHMe (0.4 mmol), HFIP (0.5 mL), 36 h, isolated yields; Isomeric ratio (A:B)
determined by isolated isomers.
[a] TsONHMe (0.8 mmol), 10 d;
[b] TsONHMe (0.8 mmol), 3 d,
[c] Isomeric ratio (A:B) determined by NMR.
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Table 5. Comparison to Another Aminating Method.
Table 6. Evaluation of the Amine Partners
Reaction conditions: arene (0.2 mmol), aminating reagents (0.8 mmol), HFIP (0.5 mL), 3 d, isolated yields.
[a] aminating reagent (0.4 mmol), 36 h.
substrates in our system showed para-selectivity,
which strongly differs from Sanford’s work,[8a] who
observed a low selectivity for the addition of a neutral
nitrogen radical onto related or equal arene systems.
This indicates that not a neutral radical but rather an
arene radical cation might be the key intermediate in
our reaction. Support for a radical process can also be
derived from the fact that self-coupling product 60a
(which cannot be explained by simple aromatic
Scheme 2. Large-scale Reaction.
Based on the obtained product distribution, a substitution), was obtained in addition to 60 during the
mechanism involving SEAr seems unlikely as the ratio amination of 1,4-dimethoxybenzene with 16
of the aminated products from monosubstituted arenes (Scheme 3). Most plausible, 60a was formed by
(17–20) are not indicative of an SEAr regioselectivity. dimerization of radical cation Int2, which can be
In general, arenes bearing electron-donating substitu- formed via a SET process from the electron-rich amine
ents afford better yields than those with electron- 60 to the electron-deficient aminating reagent 16.
withdrawing groups, consistent with a pathway involv- Besides, an electron charge transfer could be involved,
ing a nitrogen-centered radical. Furthermore, most as 16 was decomposed after the addition of mesitylene
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Table 7. Application in Late-stage Functionalization and Related Reactions
Reaction conditions: arene (0.2 mmol), TsONHMe (0.4 mmol), HFIP (0.5 mL), 36 h–5 d, isolated yields; Isomeric distribution (A:
B) determined by isolated isomers.
[a] TsONHMe (0.8 mmol), 36 h–3 d.
Scheme 3. Proposed Self-coupling of Aniline-derived Inter-
mediates.
in HFIP, and aniline was formed gradually; at the same
time, the reaction became yellow from colorless (16 is
stable in d2-HFIP for several hours; for mesitylene, the
aromatic-H could be deuteriated in d2-HFIP; for time-
dependent NMR, see Figure 1 and Figures S3–S7).
In order to obtain more evidence, a series of
mechanistic experiments was carried out. The observed
bathochromic shifts (absorption band around 400–
Figure 1. Overlay of 1H NMR Samples (d2-HFIP) Taken during
the Reaction. Product signals for aromatic-H highlighted in red,
signals for the MeNH group in blue.
700 nm) in the UV/Vis spectra (Figure 2a, Figures S8– after a short period Int2 dominates the UV/Vis spectra.
S9 and S12–S13) upon addition of 16 to 4-tert- This was verified by the fact that the same bath-
butylanisole and 1,4-dimethoxybenzene, are consistent ochromic shifts (450–500 nm) are visible for the
with reports from Oka[15] on the 4-tert-butylanisole reaction between 1,4-dimethoxybenzene, treated with
radical cation (Int4) and the 1,4-dimethoxybenzene 16 after 50 min, and by the treatment of 60 with 16
radical cation (Int1). The UV/Vis spectra at different after 5 min (Figure 2b and Figure S10–S11). The
reaction times for the reaction of 1,4-dimeth- detection of these intermediate species Int1 and Int2
oxybenzene and 16 (Figure 2b and Figure S9) showed strongly supports the formation of arene radical cations
that at early reaction stages Int1 is detected, while in our system.
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Figure 2. CT UV/Vis Bands of TsONHMe with Different Arenes. Figure 2 a. UV/Vis bands of Int1 (spectrum measured in UV1 at
10 min under air) and Int4 (spectrum measured in UV3 (4-tert-butylanisole and 16 in HFIP under air) at 3 min under air),
Figure 2b. Time-dependent UV/Vis bands of UV1 (16 with 1,4-dimethoxybenzene in HFIP under air) and Int2 (spectrum measured
in UV2 after 2 min under air.
EPR spectra of various samples (Figure 3 and tion on the reaction mechanism, specifically the
Figure S16–S19) were recorded to get more informa- radicals involved (see Scheme 3). Interestingly, reac-
Figure 3. EPR Spectra of Different Radicals. Figure 3a. EPR spectrum: 16 with 1,4-dimethoxybenzene in HFIP; Figure 3b. EPR
spectrum: 16 with 2,5-dimethoxy-N-methylaniline 60 in HFIP; Figure 3c. EPR spectrum: 16 with 1,4-dimethoxybenzene and
DMPO in HFIP; Figure 3d. EPR spectrum: 1,4-dimethoxybenzene in 96% conc.H2SO4 (see Supporting Information for details).
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tion of both 1,4-dimethoxybenzene and 2,5-dimethoxy- concerted mechanism[12a]). This provides evidence for
N-methylaniline with TsONHMe yielded the same the formation of an aminyl radical during the reaction
product (Figures 3a and 3b), i.e. Int1 decays rapidly course. BHT was also aminated by 16 with the same
and cannot be trapped and observed under our yield even in the absence of mesitylene, suggesting
experimental conditions. The low stability of Int1 is in BHT is a better donor than mesitylene.
line with the results from UV-vis spectroscopy. Our
Consequently, we hypothesize that a single elec-
attempts to trap an aminyl radical under Ar in presence tron-transfer (SET) is initiating the CÀ H amination
of DMPO as radical trap[15] failed. However, the reaction. To evaluate the possibility of an SET process,
instability of Int1 in the reaction mixture is further cyclic voltammetry studies were done for TsONHMe
supported by the spectrum of Int1 as produced and TsONHBoc (for potentials of other arene sub-
according to literature[16] and the corresponding spec- strates, see Nicewicz’s work[18]) (Table S2, Figur-
trum is shown in Figure 3c. That is, the high decay rate es S20–S21). TsONHMe showed a reduction wave at
of Int1 under the reaction conditions is due to the À 1.06 V (CH3CN, vs. Ag), confirming that TsONHMe
radical recombination involving the aminyl radical. can serve as an SET oxidant for electron-rich aromatic
The coupling that is well resolved on some of the lines systems. Hence, the formation of an initial radical
in spectrum 3d indicates that the radical couples to the anion is a reasonable process, which then in a fast
four phenyl H atoms, and the much smaller additional reaction delivers the aminyl radical (trapped by BHT)
splitting is due to the H atoms of the two OMe groups. via mesolysis, a process reported for these types of
The general pattern with an 11 line spectrum and the nitrogen radicals by Macmillan[19] and Gaunt.[20]
observed intensity distribution was interpreted as being
the result of two isomers of the para-dimethoxy
Theoretical Calculations
radical.[17] The only radical in our proposed mechanism
in Scheme 3, following the decay of Int1 is Int2. With As already mentioned, oxygen plays an important role
optimized conditions, fine-structure on each of the 11 in our reaction. This is manifested by the observation
transitions is resolved, indicating that there is a very that, in contrast to the experiments under open flask
small coupling to the 6 OMe hydrogen atoms just as in conditions discussed above, under an argon atmosphere
Int1 (Figure 3c). The observed 11 transitions in the almost no bathochromic shifts were detected if 4-tert-
spectra of Figures 3a, 3b and 3c assigned to Int2, butylanisole or 1,4-dimethoxybenzene were added to
therefore must be due to the aniline N and H atoms, 16 (Figures S14, S15). This verifies, that oxygen
the three aromatic H atoms and the NHCH3 group. The accelerates the formation of radical cations in our
splitting pattern and intensity distribution suggest that reaction system, a yet unreported phenomenon in the
the hyperfine coupling to all H atoms is approx. field of amination chemistry with or without metals.
identical with an approx. double as large coupling to
To further shed light on this observation, geometry
N. Additional support was gained by radical trapping optimizations for a hypothetical “sandwich-like” com-
experiments (Scheme 4 and Scheme S3): the reaction plex, consisting of TsONHMe, 1,4-dimethoxybenze
was almost totally inhibited when TEMPO or BHT and molecular oxygen, were conducted. The two
were used as radical scavenger, suggesting that radical energetically lowest structures found (Figure 4), which
species are present in the reaction. The postulated differ in less than 0.5 kcal/mol, were used for the
aminyl radical, formed after the SET process via further analysis of the electron-transfer step.
mesolysis, was efficiently trapped by BHT (product
For both structures respectively, a configuration
120, which also could have been formed by Bower’s interaction (CI) hamiltonian (in an orthogonal basis)
was constructed based on states generated through
constrained density-functional theory (CDFT). By
using a two-state model (i->f) for the electron transfer
between 1,4-dimethoxybenzene and TsONHMe the
Figure 4. TsONHMe-oxygen-1,4-dimethoxybenzene
“Sand-
Scheme 4. Radical Trapping Experiments.
wich-like” Complex.
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resulting off-diagonal element Hif can be analyzed and als. A related involvement of an oxygen mediated
quantified as the coupling element of the electron bridging state for a triplet excitation energy transfer
transfer process[21] (Figure 5). Within Marcus’ theory, process was reported by Valkunas group.[22] This theory
the rate of an electron transfer process is quadratically is also in line with GC kinetic results: at the early
dependent on the aforementioned coupling element. By stage, under dioxygen the reaction is faster than under
taking into account a third state for the upper analyzed dinitrogen atmosphere, and under air (open flask)
“Sandwich-like” complexes by, explicitly involving faster than under dinitrogen; the final yields according
oxygen via an oxygen mediated bridging state v, a to GC are the essentially the same (Figure 6 and
threefold increase in magnitude of the coupling Figure S22, S23).
element Hif (for both of the considered conformers)
In conclusion, we propose that the reaction follows
resulted and, directly correlated to this, the efficiency an outer-sphere SET pathway (Scheme 5): A charge-
of the electron transfer process increased. In line with transfer complex (CT complex) between the arene and
the experimental observations, this theoretically veri- the electron-deficient hydroxylamine derivative is
fies that the bridging state, available through the formed first and then an oxygen-accelerated outside
presence of oxygen, has an accelerating effect on the SET from the arene to 16 generates an arene radical
electron transfer step between the two starting materi- cation (stabilized by HFIP). A following mesolysis of
the weak NÀ O bond then affords an aminyl radical (or
ammonium radical, protonated by a little acid in
HFIP). Then recombination of the benzene radical
cation and the aminyl radical (which due to the charge
transfer event are in close proximity) afford a Wheland
complex (σ-complex), a common intermediate for SEAr
reactions in polar solvents. Finally, this is irreversibly
deprotonated to form the aminated product.
To gain additional mechanistic insight a KIE
experiment with one equimolar mixture of toluene and
d8-toluene was conducted (Scheme 6 and Scheme S4).
The ratio of KH/KD is 1:1, indicating that CÀ H
cleavage is not the rate-determining step. Besides, for
1,3,5-tri-tert-butylbenzene, instead of substitution of a
proton, one tert-butyl group was eliminated
(Scheme S5).
Figure 5. CDFI-CI Hamiltonian Matrices. Resulting CDFT-CI
Hamiltonian matrices (PBE50/pcseg-1) and the resulting elec-
tron transfer coupling element Hif resulting from the two-state
(left) and three-state model (right).
Scheme 5. Proposed Reaction Mechanism of the CÀ N Bond
Formation.
Figure 6. Time/Conversion Profiles of the Reaction under either
Dioxygen, Air or Dinitrogen. Reaction conditions: mesitylene
(0.2 mmol), TsONHMe (0.4 mmol) and nitrobenzene
(0.2 mmol; internal standard) in 0.5 mL HFIP at r.t. under O2 or
air or N2.
Scheme 6. Kinetic Isotope Effect Experiment.
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Bruker Avance-III-400, Bruker Avance-III-500, Bruker Avance-
III-600. Chemical shifts are reported in ppm with the solvent
resonance as the internal standard. For H NMR: CDCl3, 7.26;
We attribute the good yield and selectivity to the
unique properties of HFIP[23] (high polarity, weak
nucleophilicity), which already were shown to have a
significant effect on reactivity and selectivity in a
variety of reactions.[24] HFIP can stabilize arene radical
cations,[25] and also a strong hydrogen-donor and
acceptor, which was supposed to lower the LUMO of
the hydroxylamine derivatives via cooperative hydro-
gen-bond interactions.[10e,26] Besides, a good yield is
also attributed to the steric hindrance of arenes, as self-
coupling products of aniline are inhibited for sterically
hindered substrates. Overamination is suppressed (ex-
1
(CD3)2SO, 2.50; CD3OD, 3.31; D2-HFIP, 4.41. For 13C NMR:
CDCl3, 77.16; (CD3)2SO, 39.52; CD3OD, 49.00. Data is
reported as follows: s=singlet, d=doublet, t=triplet, q=
quartet, m=multiplet, brs=broad singlet, dd=doublet of
doublets, td=triplet of doublets; coupling constants in Hz;
integration. Mass spectra (MS and HRMS) were determined
in the chemistry department of the University Heidelberg under
the direction of Dr. J. Gross. EI+ -spectra were measured on a
JOEL JMS-700 spectrometer. For ESI+ -spectra a Bruker
ApexQu FT-ICR-MS spectrometer was applied. Gas Chroma-
cept for 60) by protonation of the formed anilines in tography/Mass Spectrometry (GC/MS) spectra were meas-
ured on two different hardware systems: 1. HP 5972 Mass
Selective Detector, coupled with a HP 5890 SERIES II plus gas
chromatography. 2. Agilent 5975 C Mass Selective Detector,
coupled with an Agilent 7890 A gas chromatography. In both
cases, as a capillary column, an OPTIMA 5 cross-linked Methyl
Silicone column (30 m×0.32 mm, 0.25 μm) was employed and
helium was used as the carrier gas. UV/Vis spectra were
recorded at room temperature on Jasco UV/VIS V-670
spectrophotometer and 1×3 cm quartz cuvette. The measure-
ments were done in HFIP. EPR spectra were carried out at
room temperature using a Bruker ELEXSYS E500 CW EPR
spectrometer, equipped with an ER 4116DM dual mode
resonator. The measurements were done in HFIP or conc.
H2SO4. Infrared Spectroscopy (IR) was processed on an FT-
IR Bruker (IF528), IR Perkin Elmer (283) or FT-IR Bruker
Vector 22. The solvent or matrix is denoted in brackets. For the
most significant bands the wave number ν (cmÀ 1) is given.
Melting points were measured in open glass capillaries in a
Büchi melting point apparatus (according to Dr. Tottoli) and
were not corrected. X-ray crystal structure analyses were
measured at the chemistry department of the University of
Heidelberg under the direction of Dr. F. Rominger on a Bruker
Smart CCD or Bruker APEX-II CCD instrument using MoÀ Kα-
radiation. Diffraction intensities were corrected for Lorentz and
polarization effects. An empirical absorption correction was
applied using SADABS based on the Laue symmetry of
reciprocal space. Hydrogen atoms were either isotropically
refined or calculated. The structures were solved and refined by
Dr. F. Rominger using the SHELXTL software package. ICP-
OES measurements were carried out using an Agilent 720
ICP-OES with charge coupled devices (CCD) simultaneous
detection systems. Plasma torch alignment was performed by
using a Mn solution (5 ug/g) at emission line 257.61 nm. Cyclic
our reaction system. This avoids the introduction of
multiple methylamine groups. Moreover, para-substi-
tution was more favored, especially only para-isomers
were formed when mono-substituted alkylbenzenes
were used as substrates, which can be explained by
electron charge transfer processes and Fukui Indices
according to Ritter’s report[8c] or determined by the
stability of the intermediate arene radical cation. We
observed this aminyl radical reactivity distinct from
the Hofmann-Löffler-Freytag reaction that easily ab-
stracts H atom from Csp3. Instead arenes with Csp3À H
functionalization are favored; and no side products are
formed based on carbon radicals.
Conclusion
We present a direct metal-free arene CÀ H amination
under mild conditions in moderate to excellent yields.
In contrast to metal-catalyzed processes the reaction is
triggered by an oxygen-accelerated SET from the
aromatic systems to the electron-deficient hydroxyl-
amine derivatives. The recombination of an arene
radical cation and an aminyl radical, which are in close
proximity, then affords the aminated products. The
methodology can be applied for the amination of a
variety of complex molecules, natural bioactive prod-
ucts and best-selling drugs. The operationally easy,
broad functional group tolerance and scalability of this
reaction make it appealing for academy and industry.
Especially noteworthy is the absence of any metal,
which makes this process especially attractive for the
use in late-stage processes of medicinal chemistry and
drug synthesis.
voltammetry (CV)was performed on
a VersaSTAT3-200
potentiostat (Princeton Applied Research). And it was carried
out using a glassy carbon working electrode, a platinum/
titanium wire auxiliary electrode, a silver wire pseudo-reference
electrode, a 0.1 M NBu4PF6 solution in N2 degassed dry
acetonitrile. Gas Chromatography (GC) was processed on HP
58090 SERIES II with a HP 1 column. Nitrogen was used as
the carrier gas.
Experimental Section
Chemicals were purchased from commercial suppliers (Sigma-
Aldrich, Alfa Aesar and TCI) and used as delivered. Dry
solvents were dispensed from solvent purification system MB
SPS-800. HFIP was used directly without further purification.
Deuterated solvents were bought from Euriso-Top. Unless
otherwise stated, all reactions and manipulations were carried
out under ambient atmosphere in new reaction vials or flasks.
NMR Spectra were recorded on a Bruker Avance-III-300,
General Procedure for the Mitsunobu Reaction –
GP 1
To a solution of PPh3 (1.0 eq) in dry THF was added DIAD
°
(1.0 eq) at 0 C under nitrogen atmosphere. A white solid was
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formed after 10 min. After 30 min, a solution of alcohol
(1.0 eq) in THF and TsONHBoc (1.0 eq) in THF were added to
+ Scholarship. P.M.S. gratefully acknowledges the Hector
Fellow Academy for generous provision of funding. S.W.
acknowledges the support by the Landesgraduiertenförderung
of the state of Baden-Württemberg. We also thank Prof. Dr.
Günter Helmchen for the discussion on the mechanism. Open
access funding enabled and organized by Projekt DEAL.
°
the mixture successively. Then the reaction was stirred at 0 C
for another 1 h, and then at room temperature overnight. The
reaction was concentrated in vacuo and purified by silica gel
chromatography with PE/EA to afford the desired product.
General Procedure for the Removal of the Boc
Group – GP 2
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To a solution of N-Boc-N-alkyl-O-tosyl hydroxylamine (1.0 eq)
°
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°
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A Metal-Free Direct Arene CÀ H Amination
Adv. Synth. Catal. 2021, 363, 1–14
T. Wang, M. Hoffmann, A. Dreuw, E. Hasagić, C. Hu, P. M.
Stein, S. Witzel, H. Shi, Y. Yang, M. Rudolph, F. Stuck, F.
Rominger, M. Kerscher, P. Comba, A. S. K. Hashmi*