Iron-Catalyzed Direct Alkylamination of Phenols with O-Benzoyl-N-alkylhydroxylamines under Mild Conditions

Article abstract of DOI:10.1002/adsc.201600700

A novel iron-catalyzed direct alkylamination reaction of phenols has been achieved with O-benzoyl-N-alkylhydroxylamines as aminating agents. This protocol provides a facile access to N-alkyl-substituted aminophenols though a radical reaction from phenols. The catalytic direct alkylamination operates at room temperature without the need of any ligands and additives to afford the desired products with excellent regioselectivity and functional group tolerance. (Figure presented.).

Full text of DOI:10.1002/adsc.201600700

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DOI: 10.1002/adsc.201600700
Iron-Catalyzed Direct Alkylamination of Phenols with
O-Benzoyl-N-alkylhydroxylamines under Mild Conditions
Lei Jia,a Sen Gao,a Junyao Xie,a and Meiming Luoa,*
a
Key Laboratory of Green Chemistry and Technology of Ministry of Education, College of Chemistry, Sichuan University,
Chengdu 610064, Peopleꢀs Republic of China
Fax : (+86)-28-8546-2021; phone: (+86)-28-8546-2021; e-mail: luomm@scu.edu.cn
Received: July 2, 2016; Revised: September 4, 2016; Published online: && &&, 0000
Supporting information for this article can be found under: http://dx.doi.org/10.1002/adsc.201600700.
Abstract: A novel iron-catalyzed direct alkylamina- and additives to afford the desired products with ex-
tion reaction of phenols has been achieved with O- cellent regioselectivity and functional group toler-
benzoyl-N-alkylhydroxylamines as aminating agents. ance.
This protocol provides a facile access to N-alkyl-sub-
stituted aminophenols though a radical reaction from
phenols. The catalytic direct alkylamination operates Keywords: alkylamination; C–H functionalization;
at room temperature without the need of any ligands iron catalysis; phenols; synthetic methods
Introduction
from limited generality (Scheme 1).[9] Patureau and
co-workers recently reported an O2-mediated dehy-
Arylamines are present in numerous natural products, drogenative amination of phenols with phenothiazines
synthetic materials and biologically active compounds, and phenoxazine in the presence of cumene [Eq. (1),
and have been greatly exploited in the area of drug Scheme 1].[9e] Bella and Jørgenson reported an orga-
discovery.[1] Among various methods for the synthesis nocatalytic amination of 2-naphthols by using diazodi-
of arylamines, the direct amination of arenes is a po- carboxylate as aminating reagent to afford substituted
tentially useful synthetic tool and has received wide- hydrazines [Eq. (2), Scheme 1].[9b] We previously de-
spread interest.[2–4] One of the key advantages of the scribed the direct ortho-amination of naphthols using
direct aromatic amination strategy, whether by oxida- N,N-disubstituted hydrazines as aminating reagents to
tive C–H/N–H coupling,[2] by electrophilic attack,[3] or provide N-unsubstituted aminonaphthols [Eq. (3),
via a nitrogen radical intermediate,[4] is the absence of Scheme 1].[9c] Direct introduction of an alkylamino
pre-activation steps for the aromatic C–H bonds, thus group onto phenols to give N-alkylaminophenols ap-
the C–N bond can be formed in a single chemical step. pears to be difficult. To the best of our knowledge,
N-Substituted aminophenols occur in a number of there is only a single report of a direct alkylamination
compounds which possess various biological proper- of phenol using N-benzoyloxypiperidine as the ami-
ties.[5] They are traditionally prepared by multiple nating reagent at 140–1458C in the presence of excess
steps such as nitration and subsequent reduction, N- boron trifluoride [Eq. (4), Scheme 1].[9a] A 20:1 molar
alkylation and/or N-arylation, which always result in ratio of phenol to N-benzoyloxypiperidine gave
low overall yields.[6] Apparently, the shortest access to a 32% yield of N-(o- hydroxyphenyl)piperidine, and
N-substituted aminophenols is the direct amination of no other phenols were examined.
phenols. However, compared to other aromatic com-
Thus, the direct amination of phenols still remains
pounds, examples of the direct amination of phenols problematic in substrate scope and reaction condi-
are scarce, possibly because the reaction selectivity is tions, and the direct alkylamination of phenols is par-
typically low for multiple reaction sites and concomi- ticularly challenging. In conjunction with our recent
tant homocoupling of phenols, C–O bond formation results on direct ortho-amination of 2-naphthols using
between two phenols, and complex oligo- and poly- N,N-disubstituted hydrazines as aminating reagents,[9c]
phenolic assemblies under oxidative conditions.[7,8] To we herein present an iron-catalyzed direct alkylami-
date, there have been only a few examples reported nation of phenols with O-benzoyl-N,N-dialkylhydrox-
for the direct amination of phenols, which often suffer ylamines under mild conditions [Eq. (5), Scheme 1].
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Table 1. Optimization of the reaction conditions.[a]
Entry
Catalyst
mol%
Solvent
Time
Yield[b]
1
2
3
4
5
6
7
8
–
–
–
–
–
–
–
–
10
10
10
10
5
DCM
MeOH
THF
30 h
30 h
30 h
30 h
17 h
13 h
24 h
15 min
1 h
4 h
1 h
7 h
15 h
41
56
32
84
41
52
69
89
76
64
80
81
79
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
Ag2O
MnO2
Cu(OAc)2
FeCl3
FeCl3
FeCl3
FeCl2
Fe2(SO4)3
Fe2O3
9
10
11
12
13
2
10
10
10
[a]
Reaction conditions: 1a (2.0 mmol), 2a (2.6 mmol), sol-
vent (4 mL), room temperature, argon.
Isolated yields [%].
[b]
matic substrates.[4a,10] In this respect, the Fe-catalyzed
highly efficient amination of phenols with O-benzoyl-
N-alkylhydroxylamines at room temperature was re-
markable and significant, which encouraged us to
carry out further explorations.
Scheme 1. Direct amination reactions of phenols.
Results and Discussion
With the optimized conditions in hand, we further
explored this FeCl3-catalyzed direct alkylamination of
Our initial efforts toward this goal focused on the re- various phenol derivatives. As shown in Table 2, sev-
action of 2-naphthol 1a with N-benzoyloxypiperidine eral 2-naphthols were firstly tested. We were pleased
2a without any catalysts in dichloromethane at room to find that 2-naphthols bearing electron-donating
temperature (Table 1). To our delight, the correspond- groups such as methyl, methoxy and hydroxy were
ing amination product 1-(piperidin-1-yl)-2-naphthol suitable substrates to afford the corresponding substi-
3a was obtained in 41% isolated yield after 30 h tuted 1-(piperidin-1-yl)-2-naphthols in good yields
(entry 1). Encouraged by this preliminary result, we (3b–3e). It was noted that only one piperidin-1-yl
then screened different solvents and found that tolu- group was introduced onto 2,7-naphthalenediol to
ene was the most suitable for this transformation (en- produce 3e. This may be attributed to the steric hin-
tries 2, 3 and 4). Subsequently, a variety of metal drance rising from the piperidin-1-yl group that is al-
oxides and salts like Ag2O, MnO2 and Cu(OAc)2 were ready situated at C-1. The mildness of the reaction
examined and shown to afford moderate yields (en- conditions accommodated an electron-withdrawing
tries 5–7) in a shorter reaction time. Gratifyingly, bromide function as well as ester and nitrile functions
when FeCl3 (10 mol%) was utilized as the catalyst, (3f–3h). Moreover, 6-hydroxyquinoline also coupled
a highly efficient alkylamination of 1a with 2a oc- with 2a at a slightly higher temperature of 408C,
curred, affording 3a in an excellent isolated yield of giving the desired product 3i in 77% yield. In addition
89% in 15 minutes (entry 8). At lower loadings of to 2-naphthols, the reaction was also applicable to
FeCl3, the product was obtained in reduced yields (en- simple electron-rich phenols. Phenol (1j), methyl phe-
tries 9 and 10). Other iron catalysts such as FeCl2, nols (1k, 1l and 1m) and 4-methoxyphenols (1n and
Fe2(SO4)3 and Fe2O3 were also explored, whereby 1o) underwent the reaction with 2a to produce the
lower yields were observed (entries 11–13). It is corresponding aminophenols (3j–3o) in moderate
worthy to note that iron salts have rarely been uti- yields along with unidentified substances of high po-
lized as catalysts in the C–H bond amination of aro- larity.
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Table 2. Scope of direct alkylamination of phenols with O-benzoylhydroxylamines.[a]
[a]
Reaction conditions: FeCl3 (0.2 mmol), 1 (2.0 mmol), 2 (2.6 mmol), toluene (4 mL), room temperature, 0.25–4.0 h, argon,
isolated yields.
[b]
Reaction conditions: FeCl3 (0.2 mmol), 1 (2.0 mmol), 2 (5.0 mmol), 408C, 3.0 h, argon, isolated yields.
We further tested the direct alkylamination of 2-
In the transition metal-catalyzed electrophilic C–H
naphthol with various O-benzoylhydroxylamines. As aminations of aromatic compounds other than phe-
expected, both N-benzoyloxymorpholine and N-ben- nols using O-benzoylhydroxylamines as aminating re-
zoyloxypyrrolidine reacted with 1a smoothly to gener- agents, a stoichiometric amount of base was often
ate the desired products 3p and 3q in 87% and 76% used to regenerate the starting active catalyst to com-
yields, respectively. It was noteworthy that the Boc- plete the catalytic cycle.[3g] It is also known that the
protected piperazine could be introduced to 2-naph- nucleophilic activity of 2-naphthol can be further im-
thols to produce the corresponding aminated products proved by the addition of a base.[7b] To our surprise,
(3r–3t) in good yields, which enable a potential appli- however, when the reaction between 1a and 2a was
cation in further functionalization. While O-benzoyl- conducted in the presence of two equivalents of Et3N
N,N-diethylhydroxylamine afforded product 3u and 10 mol% of FeCl3, no desired product 3a was ob-
in 83% yield, O-benzoyl-N,N-dibutylhydroxylamine tained at all even after 30 h at room temperature [Eq.
and O-benzoyl-N-butyl-N-(4-pentenyl)hydroxylamine (6), Scheme 2]. This observation suggested that the
gave products 3v and 3w in 27% and 25% yields, re- present Fe-catalyzed direct alkylamination of phenols
spectively, probably due to the steric hindrance of seemed not to go through an electrophilic amination
the two long alkyl groups. The reaction is not applica- process. To gain further mechanistic information
ble to N-monosubstituted-O-benzoylhydroxylamine about this transformation, a radical-trapping experi-
under the same reaction conditions (3x).
ment was carried out. In the presence of one equiva-
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Scheme 3. Proposed reaction mechanism.
through path A in which the reaction is initiated by
single electron transfer from phenol 1 to O-benzoyl-
hydroxyamine 2 to generate benzoyloxyl radical 4 and
phenoxyl radical which may be written in two reso-
nance structures 5 and 6. The C-radical 6 subsequent-
Scheme 2. Control experiments for mechanism study.
lent of TEMPO, no product 3a was obtained under ly undergoes a radical substitution reaction with O-
the standard conditions [Eq. (7), Scheme 2], suggest- benzoylhydroxlamine 2 to produce benzoyloxyl radi-
ing the reaction might occur via a radical process. We cal 4 and the aminated intermediate 7 which isomeriz-
then performed the reaction of 2-naphthol with O- es immediately to the final product 3. Benzoyloxyl
benzoyl-N-butyl-N-(4-pentenyl)hydroxylamine under radical 4 can then perform the propagation by oxidiz-
the standard conditions, which gave the aminated ing phenol 1 to phenoxyl radical 5 or 6. In the pres-
product 3w in 25% yield and no pyrrolidine deriva- ence of the iron catalyst, the reaction may proceed
tives from an aminyl radical cyclization [Eq. (8), through path B where phenoxyl radical 5 or 6 may
Scheme 2].[11] This result implied that an aminyl radi- also be produced from 1 by the oxidation of
cal-involved pathway was less likely. Finally, we found Fe(III).[12] The produced Fe(II) is reoxidized to
that the reaction was significantly accelerated (15 h Fe(III) by benzoyloxyl radical 4 and/or O-benzoylhy-
vs. 30 h, Table 1, entry 4) by benzoyl peroxide (BPO, droxyamines 2. Then the radical substitution reaction
10 mol%) [Eq. (9), Scheme 2], implicating that a radi- between radical 6 and O-benzoylhydroxlamine 2 pro-
cal process and benzoyloxyl radicals might be in- duces benzoyloxyl radical 4 and the aminated inter-
volved.
mediate 7 which isomerizes to the final product 3 just
It is accepted that FeCl3 can oxidize phenols to phe- as in path A. The effect of iron catalyst as an oxidant/
noxyl radicals.[12] Iron(II) can be oxidized to iron(III) initiator thus significantly promotes the reaction.
[13]
by BPO
and N-benzoyloxypiperidine (see the Sup-
porting Information).
Based on these literature results and the above- Conclusions
mentioned experimental observations,
a putative
mechanism may be proposed as shown in Scheme 3. In conclusion, a novel Fe-catalyzed direct alkylamina-
In the absence of a catalyst, the reaction may go tion reaction of phenols under mild conditions has
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118.4, 116.3, 107.5, 55.3, 52.4, 27.8, 24.2; HR-MS (ESI): m/
z=258.1493, calcd. for C16H20NO2 [M+H]+: 258.1489.
7-Methoxy-1-(piperidin-1-yl)naphthalen-2-ol (3d): Eluent:
petroleum ether/ethyl acetate (20:1); yield: 84%; white
been successfully established. The important feature
of this strategy is direct furnishing N-alkyl-substituted
aminophenols though a radical process which is ac-
complished via iron-catalyzed reaction between phe-
nols and O-benzoyl-N- alkylhydroxylamines. The re-
action proceeds smoothly at room temperature to
afford a number of N-alkyl-substituted aminophenols
in modest to excellent yields without the need of any
ligands and additives. Preliminary mechanistic studies
revealed that radicals were involved in the overall
process and FeCl3 might act as an initiator and
a Lewis acid as well as to promote the transformation.
The mild conditions and efficiency of the reaction
render the present method attractive for future appli-
cations.
1
solid; mp 82.0–83.08C; H NMR (400 MHz, CDCl3): d=8.35
(br s, 1H), 7.70 (d, J=8.9 Hz, 1H), 7.57 (d, J=8.7 Hz, 1H),
7.28 (s, 1H), 7.12 (d, J=8.7 Hz, 1H), 6.98 (dd, J=8.9 Hz,
2.4 Hz, 1H), 3.96 (s, 3H), 3.61 (t, J=11.7 Hz, 2H), 3.04 (d,
J=12.1 Hz, 2H), 1.72–1.99 (m, 5H), 1.43–1.51 (m, 1H);
13C NMR (100 MHz, CDCl3): d=157.6, 152.1, 133.3, 130.9,
129.1, 127.9, 124.8, 114.2, 113.4, 101.9, 55.3, 51.9, 27.8, 24.3;
HR-MS (ESI): m/z=258.1493, calcd. for C16H20NO2
[M+H]+: 258.1489.
1-(Piperidin-1-yl)naphthalene-2,7-diol (3e): Eluent: petro-
leum ether/ethyl acetate (10:1); yield: 71%; colorless oil;
1H NMR (400 MHz, CDCl3): d=7.67 (d, J=8.8 Hz, 1H),
7.53 (d, J=8.8 Hz, 1H), 7.30 (d, J=1.8 Hz, 1H), 7.08 (d, J=
8.8 Hz, 1H), 6.88 (dd, J=8.8 Hz, 2.2 Hz, 1H), 3.54 (td, J=
11.7 Hz, 2.2 Hz, 2H), 2.95 (d, J=11.5 Hz, 2H), 1.66–1.92 (m,
5H), 1.38–1.47 (m, 1H); 13C NMR (100 MHz, CDCl3): d=
153.6, 152.1, 133.3, 131.3, 128.8, 128.0, 124.9, 114.1, 113.4,
104.9, 51.8, 27.8, 24.1; HR-MS (ESI): m/z=244.1336, calcd.
for C15H18NO2 [M+H]+: 244.1332.
Experimental Section
General Procedure for Aminations
Ethyl 6-hydroxy-5-(piperidin-1-yl)-2-naphthoate (3f):
Eluent: petroleum ether/ethyl acetate (5:1); yield: 71%;
white solid; mp 88.0–90.08C; H NMR (400 MHz, CDCl3):
FeCl3 (32 mg, 0.2 mmol) and phenol (1) (2 mmol) were
placed in a 20-mL two-necked reaction flask which was
filled with argon. A solution of O-benzoyl hydroxylamine
(2) (2.6 mmol) in toluene (4.0 mL) was added to the flask.
The solution was stirred at ambient temperature for 15 min
to 3 h. Et3N (0.5 mL) was added. The product was purified
by silica gel column chromatography with hexanes/ethyl ace-
tate (20:1) as the eluent to afford the desired target product
(3).
1-(Piperidin-1-yl)naphthalen-2-ol (3a): Eluent: petroleum
ether/ethyl acetate (20:1); yield: 89%; white solid; mp 62.0–
64.08C; 1H NMR (400 MHz, CDCl3): d=8.30 (br s, 1H),
7.97 (d, J=8.5 Hz, 1H), 7.77 (d, J=8.2 Hz, 1H), 7.61 (d, J=
8.8 Hz, 1H), 7.41 (t, J=8.0 Hz, 1H), 7.24 (d, J=8.5 Hz,
2H), 3.58 (td, J=11.7, 1.9 Hz, 2H), 2.99 (d, J=11.2 Hz,
2H), 1.68–1.82 (m, 5H), 1.42–1.53 (m, 1H); 13C NMR
(100 MHz, CDCl3): d=151.6, 132.2, 129.9, 129.5, 129.4,
128.1, 125.8, 122.4, 122.3, 116.0, 52.3, 27.8, 24.2; HR-MS
(ESI): m/z=228.1387, calcd. for C15H18NO [M+H]+:
228.1383.
1
d=8.55 (s, 1H), 8.52 (br s, 1H), 8.00–8.05 (m, 2H), 7.77 (d,
J=8.8 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H), 4.35 (q, J=7.2 Hz,
2H), 3.59 (td, J=11.7 Hz, 2.5 Hz, 2H), 3.00 (d, J=11.1 Hz,
2H), 1.72–1.99 (m, 5H), 1.50–1.58 (m, 1H), 1.46 (t, J=
7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=166.8, 153.8,
134.4, 132.4, 130.1, 129.8, 128.4, 125.4, 124.3, 122.3, 116.7,
60.9, 52.2, 27.8, 24.1, 14.4; HR-MS (ESI): m/z=300.1602,
calcd. for C18H22NO3 [M+H]+: 300.1594.
6-Hydroxy-5-(piperidin-1-yl)-2-naphthonitrile
(3g):
Eluent: petroleum ether/ethyl acetate (10:1); yield: 81%;
1
white solid; mp 112.0–114.08C; H NMR (400 MHz, CDCl3):
d=8.44 (br s, 1H), 8.08 (s, 1H), 7.95 (d, J=8.8 Hz, 1H),
7.61 (d, J=8.8 Hz, 1H), 7.47 (d, J=8.7 Hz, 1H), 7.28 (d, J=
8.8 Hz, 1H), 3.44 (t, J=11.5 Hz, 2H), 2.90 (d, J=11.3 Hz,
2H), 1.63–1.81 (m, 5H), 1.40–1.47 (m, 1H); 13C NMR
(100 MHz, CDCl3): d=154.5, 135.5, 130.3, 129.4, 128.9,
128.4, 126.4, 123.3, 119.6, 117.9, 105.6, 52.3, 27.7, 24.0; HR-
MS (ESI): m/z=253.1339, calcd. for C16H17N2O [M+H]+:
253.1335.
6-Methyl-1-(piperidin-1-yl)naphthalen-2-ol (3b): Eluent:
petroleum ether/ethyl acetate (20:1); yield: 89%; white
1
6-Bromo-1-(piperidin-1-yl)naphthalen-2-ol (3h): Eluent:
petroleum ether/ethyl acetate (20:1); yield: 88%; white
solid; mp 116.0–117.08C; H NMR (400 MHz, CDCl3): d=
8.23 (br s, 1H), 7.89 (d, J=8.6 Hz, 1H), 7.55(s, 1H), 7.53 (d,
J=9.8 Hz 1H), 7.26 (d, J=8.5 Hz, 1H), 7.21 (d, J=8.7 Hz,
1H), 3.58 (t, J=10.6 Hz, 2H), 2.99 (d, J=10.9 Hz, 2H), 2.45
(s, 3H), 1.69–1.94 (m, 5H), 1.43–1.56 (m, 1H); 13C NMR
(100 MHz, CDCl3): d=150.8, 131.7, 130.2, 129.8, 128.4,
128.0, 127.4, 122.2, 115.9, 52.3, 27.8, 24.2, 21.3; HR-MS
(ESI): m/z=242.1541, calcd. for C16H20NO [M+H]+:
242.1539.
1
solid; mp 103.0–105.08C; H NMR (400 MHz, CDCl3): d=
8.30 (br s, 1H), 7.95 (d, J=2.0 Hz, 1H), 7.87 (d, J=9.1 Hz,
1H), 7.56 (d, J=8.8 Hz, 1H), 7.50 (dd, J=9.0 Hz, 2.1 Hz,
1H), 7.28–7.30 (m, 1H), 3.54 (td, J=11.7 Hz, 2.6 Hz, 2H),
3.00 (d, J=12.2 Hz, 2H), 1.72–1.98 (m, 5H), 1.46–1.60 (m,
1H); 13C NMR (100 MHz, CDCl3): d=151.9, 131.2, 130.6,
130.1, 129.0, 127.2, 124.0, 117.1, 115.9, 52.3, 27.8, 24.1; HR-
MS (ESI): m/z=306.0496, calcd. for C15H17BrNO [M+H]+:
306.0488.
6-Methoxy-1-(piperidin-1-yl)naphthalen-2-ol (3c): Eluent:
petroleum ether/ethyl acetate (20:1); yield: 87%; white
1
5-(Piperidin-1-yl)quinolin-6-ol (3i): Eluent: petroleum
ether/ethyl acetate (5:1); yield: 71%; light yellow solid: mp
solid; mp 111.0–113.08C; H NMR (400 MHz, CDCl3): d=
8.15 (br s, 1H), 7.92 (d, J=7.5 Hz, 1H), 7.55 (d, J=8.8 Hz,
1H), 7.25 (d, J=8.8 Hz, 1H), 7.13–7.16 (m, 2H), 3.91 (s,
3H), 3.58 (t, J=11.6 Hz, 2H), 3.02 (d, J=11.5 Hz, 2H),
1.71–1.97 (m, 5H), 1.44–1.52 (m, 1H); 13C NMR (100 MHz,
CDCl3): d=155.0, 149.8, 130.4, 130.3, 127.6, 126.6, 123.8,
1
160.0–162.08C; H NMR (400 MHz, CDCl3): d=8.72 (d, J=
3.3 Hz, 1H), 8.39 (d, J=8.6 Hz, 1H), 8.21 (br s, 1H), 7.97
(d, J=9.0 Hz, 1H), 7.50 (d, J=9.2 Hz, 1H), 7.35 (dd, J=
8.4 Hz, 4.3 Hz, 1H), 3.50 (t, J=11.4 Hz, 2H), 3.03 (d, J=
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11.0 Hz, 2H), 1.70–1.88 (m, 5H), 1.44–1.54 (m, 1H);
13C NMR (100 MHz, CDCl3): d=151.8, 146.7, 144.2, 130.6,
129.5, 129.2, 127.3, 120.4, 119.4, 52.6, 27.7, 24.1; HR-MS
(ESI): m/z=229.1343, calcd. for C14H17N2O [M+H]+:
229.1335.
2-(Piperidin-1-yl) phenol (3j): Eluent: petroleum ether/
ethyl acetate (10:1); yield: 25%; white solid; mp 69.0–
70.08C; 1H NMR (400 MHz, CDCl3): d=7.14 (dd, J=
7.8 Hz, 1.4 Hz, 1H), 7.05 (td, J=7.9, 1.5 Hz, 1H), 6.93 (dd,
J=8.0 Hz, 1.4 Hz, 1H), 6.84 (td, J=7.6 Hz, 1.4 Hz, 1H),
2.80 (t, J=5.4 Hz, 4H), 1.74 (m, 4H), 1.60 (d, J=5.0 Hz,
2H); 13C NMR (100 MHz, CDCl3): d=151.5, 140.4, 126.0,
121.3, 119.8, 113.7, 54.1, 26.8, 23.9; HR-MS (ESI): m/z=
178.1230, calcd. for C11H16NO [M+H]+: 178.1226.
4-Methyl-2-(piperidin-1-yl)phenol (3k): Eluent: petroleum
ether/ethyl acetate (10:1); yield: 40%; colorless oil;
1H NMR (400 MHz, CDCl3): d =6.95 (s, 1H), 6.85 (t, J=
2.0 Hz, 2H), 2.79 (t, J=5.6 Hz, 2H), 2.27 (s, 3H), 1.69–1.75
(m, 4H), 1.58–1.59 (m, 2H); 13C NMR (100 MHz, CDCl3):
d=149.0, 140.1, 129.0, 126.3, 121.8, 113.3, 54.1, 26.8, 24.0,
20.8; HR-MS (ESI): m/z=192.1378, calcd. for C12H18NO
[M+H]+: 192.1383.
CDCl3): d=151.6, 131.8, 129.6, 129.5, 128.8, 127.9, 126.2,
122.7, 121.9, 116.1, 68.5, 50.9; HR-MS (ESI): m/z=230.1182,
calcd. for C14H16NO2 [M+H]+: 230.1176.
1-(Pyrrolidin-1-yl)naphthalen-2-ol (3q): Eluent: petrole-
um ether/ethyl acetate (10:1); yield: 76%; white solid; mp
90.0–92.08C; 1H NMR (400 MHz, CDCl3): d=7.85 (d, J=
8.2 Hz, 1H), 7.73 (d, J=8.5 Hz, 1H), 7.67 (d, J=8.8 Hz,
1H), 7.46 (d, J=8.0 Hz, 1H), 7.27–7.33 (m, 3H), 3.41 (s,
4H), 2.23 (s, 4H); 13C NMR (100 MHz, CDCl3): d=153.3,
130.6, 129.8, 128.1, 126.1, 125.9, 122.4, 121.3, 115.8, 51.7,
26.5; HR-MS (ESI): m/z=214.1232, calcd. for C14H16NO
[M+H]+: 214.1226.
tert-Butyl 4-(2-hydroxynaphthalen-1-yl)piperazine-1-car-
boxylate (3r): Eluent: petroleum ether/ethyl acetate (10:1);
yield: 72%; white solid; mp 164.0–166.08C; 1H NMR
(400 MHz, CDCl3): d=8.10 (br s, 1H), 7.94 (d, J=8.5 Hz,
1H), 7.82 (d, J=8.1 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.47
(t, J=7.4 Hz, 7.27–7.34 (m, 2H), 4.25 (s, 2H), 3.75 (t, J=
11.0 Hz, 2H), 3.16 (s, 2H), 2.97 (d, J=11.0 Hz, 2H), 1.55 (s,
9H); 13C NMR (100 MHz, CDCl3): d=154.8, 151.4, 131.9,
129.5, 129.4, 128.8, 128.2, 126.2, 122.7, 121.9, 116.2, 80.2,
50.7, 28.5; HR-MS (ESI): m/z=329.1865, calcd. for
C19H25N2O3 [M+H]+: 329.1860.
3,5-Dimethyl-2-(piperidin-1-yl)phenol (3l): Eluent: petro-
leum ether/ethyl acetate (10:1); yield: 60%; colorless oil;
1H NMR (400 MHz, CDCl3): d=6.63 (s, 1H), 6.39 (s, 1H),
3.14–3.20 (m, 2H), 2.83–2.86 (m, 2H), 2.34 (s, 3H), 2.24 (s,
3H), 1.84–1.87 (m, 1H), 1.69–1.75 (m, 2H); 1.62–1.69 (m,
2H); 13C NMR (100 MHz, CDCl3): d=147.2, 139.6, 128.1,
127.8, 122.6, 119.0, 54.1, 26.9, 24.0, 20.8, 15.8; HR-MS (ESI):
m/z=206.1542, calcd. for C13H20NO [M+H]+: 206.1539.
2,4-Dimethyl-6-(piperidin-1-yl)phenol (3m): Eluent: pe-
troleum ether/ethyl acetate (20:1); yield: 65%; colorless oil;
1H NMR (400 MHz, CDCl3): d=6.80 (s, 1H), 6.75 (s, 1H),
2.77 (t, J=4.8 Hz, 4H), 2.23 (s, 6H), 1.69–1.75 (m, 4H), 1.58
(s, 2H); 13C NMR (100 MHz, CDCl3): d=147.2, 139.6, 128.1,
127.8, 122.6, 119.0, 54.1, 26.9, 24.0, 20.8, 15.8; HR-MS (ESI):
m/z=206.1540, calcd. for C13H20NO [M+H]+: 206.1539.
4-Methoxy-2-(piperidin-1-yl)phenol (3n): Eluent: petrole-
um ether/ethyl acetate (10:1); yield: 62%; colorless oil;
1H NMR (400 MHz, CDCl3): d=6.85 (d, J=8.8 Hz, 1H),
6.73 (d, J=2.8 Hz, 1H), 6.61 (dd, J=8.8 Hz, 2.8 Hz, 1H),
3.75 (s, 3H), 2.78 (t, J=8.8 Hz, 4H), 1.70–1.74 (m, 4H), 1.58
(d, J=4.8 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=153.0,
145.4, 140.9, 113.7, 110.1, 108.1, 55.8, 53.9, 26.8, 23.9; HR-
MS (ESI): m/z=208.1335, calcd. for C12H18NO2 [M+H]+:
208.1332.
tert-Butyl 4-(2-hydroxy-6-methylnaphthalen-1-yl)pipera-
zine-1-carboxylate (3s): Eluent: petroleum ether/ethyl ace-
tate (10:1); yield: 68%; white solid; mp 144.0–145.08C;
1H NMR (400 MHz, CDCl3): d=7.93 (br s, 1H), 7.84 (d, J=
8.7 Hz, 1H), 7.59–7.61 (m, 2H), 7.28–7.31 (m, 1H), 7.24 (d,
J=8.8 Hz, 1H), 4.23 (m, 2H), 3.71 (td, J=11.6 Hz, 2.8 Hz,
2H), 3.12 (m, 2H), 2.93 (d, J=11.4 Hz, 2H), 2.48 (s, 3H),
1.55 (s, 9H); 13C NMR (100 MHz, CDCl3): d=154.8, 150.7,
132.1, 130.0, 129.8, 128.4, 128.2, 128.0, 121.8, 116.1, 80.1,
50.7, 28.5, 28.4, 21.2; HR-MS (ESI): m/z=343.2022, calcd.
for C20H27N2O3 [M+H]+: 343.2016.
tert-Butyl 4-(6-bromo-2-hydroxynaphthalen-1-yl)pipera-
zine-1-carboxylate (3t): Eluent: petroleum ether/ethyl ace-
tate (10:1); yield: 69%; white solid; mp 149.0–150.08C;
1H NMR (400 MHz, CDCl3): d=7.94–7.97 (m, 2H), 7.80 (d,
J=9.1 Hz, 1H), 7.57 (d, J=9.2 Hz, 1H), 7.50 (dd, J=6.8 Hz,
2.6 Hz, 1H), 7.28–7.30 (m, 1H), 4.24 (m, 2H), 3.65 (td, J=
11.6 Hz, 2.9 Hz, 2H), 3.14 (m, 2H), 2.93 (d, J=11.4 Hz,
2H), 1.55 (s, 9H); 13C NMR (100 MHz, CDCl3): d=155.0,
151.8, 131.3, 129.7, 129.4, 128.5, 127.9, 123.6, 119.2, 117.4,
116.3, 80.6, 50.7, 28.5; HR-MS (ESI): m/z=407.0972, calcd.
for C19H24BrN2O3 [M+H]+: 407.0965.
1-(Diethylamino)naphthalen-2-ol (3u): Eluent: petroleum
ether/ethyl acetate (20:1); yield: 83%; light yellow solid; mp
35.0–37.08C; 1H NMR (400 MHz, CDCl3): d=8.15 (br s,
1H), 7.72 (t, J=8.0 Hz, 2H), 7.56 (d, J=8.8 Hz, 1H), 7.33
(t, J=7.4 Hz, 1H), 7.16–7.21 (m, 2H), 3.20–3.36 (m, 4H),
0.93 (t, J=7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3): d=
153.8, 132.0, 129.7, 129.6, 128.2, 125.8, 125.6, 122.4, 121.9,
115.7, 49.3, 14.6; HR-MS (ESI): m/z=216.1388, calcd. for
C14H18NO [M+H]+: 216.1383.
2-Chloro-4-methoxy-6-(piperidin-1-yl)phenol
(3o):
Eluent: petroleum ether/ethyl acetate (10:1); yield: 46%;
1
colorless oil; H NMR (400 MHz, CDCl3): d=6.66 (s, 1H),
6.63 (s, 1H), 3.74 (s, 3H), 2.78 (t, J=5.2 Hz, 4H), 1.70–1.75
(m, 4H), 1.56–1.60 (m, 2H); 13C NMR (100 MHz, CDCl3):
d=152.7, 141.9, 118.6, 110.3, 107.1, 55.8, 53.8, 26.6, 23.8;
HR-MS (ESI): m/z=242.0938, calcd. for C12H17ClNO2
[M+H]+: 242.0942.
1-Morpholinonaphthalen-2-ol (3p): Eluent: petroleum
ether/ethyl acetate (10:1); yield: 87%; white solid; mp
162.0–164.08C; H NMR (400 MHz, CDCl3): d=8.11 (br s,
1H), 8.04 (d, J=8.5 Hz, 1H), 7.83 (d, J=8.1 Hz, 1H), 7.70
(d, J=8.8 Hz, 1H), 7.49 (t, J=7.0 Hz, 1H), 7.33 (t, J=
7.9 Hz, 1H), 7.27–7.29 (m, 1H), 4.09 (d, J=11.7 Hz, 2H),
3.95 (td, J=11.4 Hz, 2.8 Hz, 2H), 3.85 (td, J=11.0 Hz,
2.0 Hz, 2H), 2.86 (d, J=11.8 Hz, 2H); 13C NMR (100 MHz,
1-(Dibutylamino)naphthalen-2-ol (3v): Eluent: petroleum
ether/ethyl acetate (20:1); yield: 27%; colourless oil;
1H NMR (400 MHz, CDCl3): d=8.11 (s, 1H), 7.75 (d, J=
8.8 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.56 (d, J=8.8 Hz,
1H), 7.34 (t, J=8.4 Hz, 1H), 7.20 (t, J=8.4 Hz, 1H), 7.18
(d, J=8.8 Hz, 1H), 3.18–3.21 (m, 4H), 1.35–1.47 (m, 2H),
1.14–1.29 (m, 6H), 0.75–0.79 (m, 6H); 13C NMR (100 MHz,
CDCl3): d=153.20, 131.71, 129.77, 129.57, 128.09, 127.41,
1
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asc.wiley-vch.de
125.83, 122.42, 122.10, 115.78, 55.82, 31.81, 20.49, 13.96; HR-
MS (ESI): m/z=272.2012, calcd. for C18H26NO [M+H]+:
272.2009.
Am. Chem. Soc. 2011, 133, 1694; f) E. J. Yoo, S. Ma, T.-
S. Mei, K. S. L. Chan, J.-Q. Yu, J. Am. Chem. Soc. 2011,
133, 7652; g) N. Matsuda, K. Hirano, T. Satoh, M.
Miura, Org. Lett. 2011, 13, 2860; h) X.-Y. Liu, P. Gao,
Y.-W. Shen, Y.-M. Liang, Org. Lett. 2011, 13, 4196;
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1-[Butyl(pent-4-en-1-yl)amino]naphthalen-2-ol
(3w):
Eluent: petroleum ether/ethyl acetate (20:1); yield: 25%;
1
colorless oil; H NMR (400 MHz, CDCl3): d=8.132 (s, 1H),
7.81 (m, 2H), 7.63 (d, J=8.8 Hz, 1H), 7.42 (t, J=6.8 Hz,
1H), 7.28 (t, J=8.0 Hz, 1H), 7.23 (d, J=8.8 Hz, 1H), 5.72
(m, 1H), 4.93 (m, 2H), 3.28 (m, 4H), 2.02 (q, J=7.2 Hz,
2H), 1.59 (m, 1H), 1.46 (m, 2H), 1.29 (m, 3H), 0.84 (t, J=
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=153.19,
138.09, 131.66, 129.78, 129.59, 128.18, 127.19, 125.89, 122.46,
122.04, 115.82, 114.87, 55.88, 55.43, 31.77, 31.44, 28.80, 20.48,
13.95; HR-MS (ESI): m/z=284.2016, calcd. for C19H26NO
[M+H]+: 284.2009.
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Acknowledgements
We gratefully acknowledge the National Natural Science
Foundation of China (21321061, 21072134 and J1103315/
J0104) and Applied Basic Research Foundation of Sichuan
Province for financial support, and the Comprehensive Train-
ing Platform of Specialized Laboratory, College of Chemis-
try, Sichuan University for NMR and MS measurements.
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8 Iron-Catalyzed Direct Alkylamination of Phenols with O-
Benzoyl-N-alkylhydroxylamines under Mild Conditions
Adv. Synth. Catal. 2016, 358, 1 – 8
Lei Jia, Sen Gao, Junyao Xie, Meiming Luo*
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These are not the final page numbers!