Synthesis of electron-deficient N1-(Hetero)aryl 3,3,5,5-tetramethyl piperazinones

Article abstract of DOI:10.1055/s-0036-1588903

An alternative synthesis of N1-(hetero)aryl 3,3,5,5-tetra-substituted piperazin-2-ones is demonstrated using a copper-mediated Goldberg arylation of a common intermediate in good to fair yields. An improved synthesis of 3,3,5,5-tetramethyl piperazin-2-one is also described. This method allows for the synthesis of substituted piperazin-2-ones which are challenging or inaccessible using traditional Bargellini chemistry.

Full text of DOI:10.1055/s-0036-1588903

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–E
letter
A
T. A. Alanine et al.
Letter
Synlett
Synthesis of Electron-Deficient N1-(Hetero)aryl 3,3,5,5-Tetramethyl
Piperazinones
Thomas A. Alanine
Stephen Stokes*
James S. Scott
R1-X
CuI (20 mol%)
R1
N
1,10-Phen (20 mol%)
K3PO4 (5 equiv)
H
N
3 steps
NH2
NH2
O
O
12 examples
yields: 17–92%
AstraZeneca, 310, Milton Rd, Milton, Cambridge CB4 0FZ, UK
steve.stokes@astrazeneca.com
DMF, 110 °C
N
H
N
H
R1 = aryl, heteroaryl
p-TsOH salt
both electron rich and deficient
Access to substrates intractable
by existing strategies
versatile intermediate
straightforward synthesis
Received: 24.08.2016
Accepted after revision: 05.10.2016
Published online: 20.10.2016
form, or directly from the corresponding trichloromethyl
carbinol), mediated by hydroxide (Scheme 1). This method-
ology, however, does not seem suitable for lactams with
electron-deficient N substituents.6 We attempted to pre-
pare pyridyl-substituted piperazinone 3a using the tradi-
tional Bargellini approach, using diamine 1a and trichloro-
methyl carbinol 2 (Scheme 1). Under these conditions,7a–c
we isolated only 2% of 3a and 61% of undesired 4. Under ba-
sic conditions, the lactam is cleaved by hydroxide leading to
amino acids which proved capricious in our attempts to cy-
clise back to the lactam.8
DOI: 10.1055/s-0036-1588903; Art ID: st-2016-b0560-l
Abstract An alternative synthesis of N1-(hetero)aryl 3,3,5,5-tetra-
substituted piperazin-2-ones is demonstrated using a copper-mediated
Goldberg arylation of a common intermediate in good to fair yields. An
improved synthesis of 3,3,5,5-tetramethyl piperazin-2-one is also de-
scribed. This method allows for the synthesis of substituted piperazin-
2-ones which are challenging or inaccessible using traditional Bargellini
chemistry.
Key words piperazin-2-ones, Bargellini, copper, Goldberg, hindered
In order to access our desired scaffolds, we opted for a
change in strategy where the base-sensitive functionality is
installed as the final step. We envisaged a divergent func-
tionalisation strategy from a common intermediate 5. The
only published synthesis of 5 is a multistep process which
gives a mixture of isomers 5 and 5′ (Scheme 2, a).4 Attempt
to use unsubstituted diamine 1b in a Bargellini process de-
livered undesired piperazinone isomer 5′′ as the only cyclic
product detected (Scheme 2, b). In this case, initial nucleo-
philic attack of the Bargellini reaction cascade occurs from
the least hindered nitrogen atom of 1b.5b This result high-
lighted the need for a removable substituent on the nitro-
gen to control regioselectivity.
We anticipated that an electron-donating group on the
amine would be beneficial for the Bargellini process. With
this in mind, we opted to use of the 2,4-dimethoxybenzyl
group (DMB). Reductive amination of diamine 1b with 2,4-
dimethoxybenzaldehyde gave a 4:1 mixture of regioiso-
meric amines in favour of 1c. This mixture was able to be
used without purification in the Bargellini step. Gratifying-
ly, 1c showed the desired regioselectivity for piperazinone
3b, isolated in 68% yield on a 1.5 g scale.
amines
Functionalised piperazines are a commonly utilized
motif in medicinal chemistry programs, with N-aryl piper-
azines representing an important class that have demon-
strated a diverse range of biological activities.1a,b A subset of
these useful heterocycles are the 3,3,5,5-tetrasubstituted
piperazin-2-ones which confer steric shielding around the
amine nitrogen. The corresponding nitroxides have found
utility as radical promoters for polymerisation processes or
as radical inhibitors to protect against damage caused by
oxidation, heat, or light,2a,f and the N-chloro derivatives
have been reported as antibacterial agents.3 Structurally re-
lated 3,3,5,5-tetrasubstituted morpholin-2-ones and related
hindered amines have also found application in recent re-
ports of aliphatic C–H activation.4 We wished to expand the
synthetically methodology in this area in order to enrich
our collection of medicinally relevant building blocks for in-
corporation into drug discovery programs and targeted
3,3,5,5-substituted piperazin-2-ones with aryl and het-
eroaryl substituents in the N1 position. Typically, these het-
erocyclic amines are prepared via the Bargellini reaction,5a,b
using a suitably substituted 1,2-diamine and a gem-dichlo-
roepoxide (usually formed in situ from a ketone and chloro-
We evaluated a range of deprotection conditions for the
removal of the DMB moiety. Surprisingly, trifluoroacetic
acid proved ineffective, as did ceric ammonium nitrate
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

B
T. A. Alanine et al.
Letter
Synlett
Traditional synthesis of 3,3,5,5-tetrasubstituted piperazinones
Incompatible if R3 = EWG
R3
R3
N
O
2
3
NH
HO
R4
R5
Cl
Cl
NaOH
6
1
R1
R2
+
R1
R4
R5
4
R25
N
Cl
NH2
H
R1, R2, R4, R5 = H
uncommon scaffold
(0.2% of piperazin-2-ones)
O
+
CHCl3
R4
R5
N
N
N
BTEAC (0.1 equiv)
50% aq. NaOH (5 equiv)
HO
Cl
Cl
Cl
N
O
NH
NH
+
CH2Cl2, 0.1 M
N
H
N
H
CO2H
0 °C to r.t., overnight
NH2
1a
2
3a (2%)
4 (61%)
Scheme 1 The Bargellini reaction is the most common route to 3,3,5,5-tetrasubstituted piperazin-2-ones; BTEAC = N-benzyl-N,N-triethylammonium
chloride
(CAN) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ), all producing only traces of product. However, posi-
tive results were obtained using stronger acids, in particu-
lar p-TsOH in refluxing toluene,9 delivered 5 as the tosylate
salt after filtration in excellent yield.
Metal-catalysed amide functionalisation was then at-
tempted. Palladium(0)-mediated functionalisation was un-
successful, possibly due to deactivation of the catalyst by
amine coordination.10 However, copper(I)-mediated Gold-
berg arylation successfully gave 3a with complete regiose-
lectivity for the lactam nitrogen. Further optimisation of
the reaction was then undertaken (Table 1).
Prior literature: McNally et al.4
O
The nature of the copper source was not found to be
critical to the reaction (Table 1, entries 1–4), and CuI was
used thereafter. Although the reaction proceeded in the ab-
sence of ligand (Table 1, entry 5), nitrogen ligands were
found to improve conversion (Table 1, entries 4–7). In par-
ticular, 1,10-phenanthroline (ligand C) gave the best results,
as N–H containing ligands (ligands A and B) showed small
amounts of ligand arylation under the reaction conditions.
O
H
N
NaN3 (2.5 equiv)
O
H2SO4
NH
(a)
CHCl3, 0 °C
N
N
H
N
H
H
5
5'
6:1 mixture, 44%
2 (2 equiv)
BTEAC (0.1 equiv)
50% aq. NaOH (5 equiv)
H
H
NH2
N
O
N
OMe
DMB
(b)
1) MeOH, 0.3 M
NH2
NH2
1b
N
H
5
N
H
5''
O
r.t., 1 h
NH
NH2
DMB
CH2Cl2, 0 °C
2) NaBH4 (2 equiv)
r.t., 1 h
NH2
O
OMe
major product
not observed
NH2
N
H
1b
1c 4:1 mixture
Proposed synthetic scheme to access
1-substituted 3,3,5,5-piperazin-2-ones
R1 = electron-poor
aryl, heteroaryl
O
after purification 9:1, 82%
R1
N
2 (2 equiv)
TEBAC (0.1 equiv)
NaOH (5 equiv)
DMB
H
H
N
O
NHPg
N
O
N
O
p-TsOH (2.2 equiv)
CH2Cl2, 0.1 M
0 °C to r.t.
PhMe, 0.3 M
120 °C
N
H
NH2
N
H
N
H
N
H
Pg = protecting group
5 94%
3b 68%
(p-TsOH salt)
Scheme 2 Literature and unsuccessful attempts to prepare 5. Proposed
strategy to access electron-deficient N1-functionalised 3,3,5,5-tetra-
substituted piperazin-2-ones.
Scheme 3 Preparation of piperazin-2-one 5; DMB = 2,4-dimethoxy-
benzyl, p-TsOH = 4-toluenesulfonic acid
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

C
T. A. Alanine et al.
Letter
Synlett
Table 1 Optimisation of the Goldberg arylation of 5
Ar(Het)-X (1.5 equiv)
CuI (0.2 equiv)
1,10-Phen (0.2 equiv)
K3PO4 (5 equiv)
R1
N
H
N
N
O
O
copper source (20 mol%)
H
DMF, 0.1 M
110 °C
N
H
N
H
ligand (20 mol%)
base (5 equiv)
N
O
N
O
N
5
3a–m
(p-TsOH salt)
solvent (0.1 M)
110 °C
N
H
N
H
I
5
3a
Cl
N
N
Cl
(1.5 equiv)
N
N
N
N
N
(p-TsOH salt)
R1
=
N
N
N
Ligand A :
Ligand B:
Ligand C:
3d 69%a 3e 17% 3f 41% 3g 70%
H
N
3a 68%
3c 69%
NH
NH
N
CN
Cl
OMe
NO2
NH
Ligand Solvent
N
N
Entry Copper
source
Base
Conversion Yield
(%)a
(%)a
1
2
CuCl
CuCN
CuTCb
CuI
A
DMF
DMF
DMF
DMF
DMF
DMF
DMF
PhMe
DMSO
dioxane
NMP
DMF
DMF
DMF
K3PO4
full
full
50
64
63
3h 84%
3i 92%
3j 62%
3k 52%
3l 53%
3m 56%
A
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
Cs2CO3
NaOt-Bu
K2CO3
Scheme 4 Substrate scope of the Goldberg arylation of 5. a For 3d,
1,10-phenanthroline was omitted and 50 mol% copper were used. For
3e–g the heteroaryl bromide was used, otherwise the aryl iodide was
employed.
3
none
4
A
75
5
CuI
none
B
55
6
CuI
75
With our desired products in hand, the hypothesis that
lactam instability was responsible for the limitations of the
Bargellini method was investigated. Substrates 3a–m were
subjected to the reaction conditions reported by Lai7a
(Scheme 5). As expected, electron-rich substrates (3b,k,l)
were stable under these basic conditions, and indeed these
are amenable to synthesis via the Bargellini method.12
Weakly electron-deficient substrates 3e,f,j,m were also re-
sistant to hydrolysis, however, substrates 3a,c,d,g,h,i all
showed hydrolysis products under these conditions, high-
lighting the utility of this new synthetic approach to this
class of substrate.
7
CuI
C
full
full
full
full
full
16
84
72
72
65
70
8
CuI
C
9
CuI
C
10
11
12
13
14
CuI
C
CuI
C
CuI
C
CuI
C
18
CuI
C
16
a As determined by 1H NMR analysis of the crude reaction mixtures with me-
sitylene as internal standard.
b CuTC = copper(I) thiophene-2-carboxylate.
In conclusion, we have reported a divergent, multistep
sequence to access piperazinones bearing an electron-with-
drawing aryl and heteroaryl substituent at the N1 posi-
tion.13–16 A key intermediate, 5, was prepared from depro-
tection of a DMB-substituted piperazinone which in turn
was prepared from reductive alkylation of a commercially
available diamine 1b. This route allows for rapid diversifica-
tion of the lactam nitrogen with aryl and heteroaryl sub-
stituents under copper catalysis, as well as access to sub-
strates that are challenging or inaccessible using other
methods. We anticipate that this synthetic approach will be
of broad utility and will encourage further study of hin-
dered amines and their incorporation into pharmaceuticals
and agrochemicals.
The choice of solvent was not found to be critical to the suc-
cess of the reaction, as both polar and apolar solvents
worked well (Table 1, entries 7–11). However the nature of
the base was crucial, as bases other than potassium phos-
phate gave poor conversion (Table 1, entries 11–14).
With the optimum reaction conditions determined (Ta-
ble 1, entry 7), the scope for R1 variation was explored. Aryl
and heteroaryl iodides were competent substrates in the
coupling, proceeding smoothly over 1–2 d at 110 °C in typi-
cally good yields (Scheme 4). However, upon moving from
iodide to bromide the reaction time lengthened significant-
ly (7–14 d, 3e,11 3f, and 3g). Substrates 3k and 3l demon-
strate that the reaction is also suitable for more electron-
rich substrates.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

D
T. A. Alanine et al.
Letter
Synlett
(6) A survey of the literature on this class of compounds shows that
out of the 730 reported examples, remarkably, only 23 bear an
electron-withdrawing group on the lactam (Scifinder substruc-
ture search excluding prophetic in patents on 3,3,5,5-tetra-
substituted scaffolds, August 2016). Included are both piper-
azin-2-ones and 2,6-diketopiperazinones.
(7) (a) Lai, J. T. J. Org. Chem. 1980, 45, 754. (b) Lai, J. T. Synthesis
1981, 40. (c) Lai, J. T. Synthesis 1982, 71.
(8) We observed intractable mixtures with multiple products from
side reactions, including decarboxylation and imidazoline for-
mation.
R1
N
R1
BTEAC (0.1 equiv)
50% aq. NaOH (5 equiv)
O
NH
CH2Cl2, 0.1 M
r.t., overnight
N
H
N
H
CO2H
3a–m
Cl
OMe
O
O
N
N
N
N
N
R1
=
N
(9) Chern, C.-Y.; Huang, Y.-P.; Kan, W. M. Tetrahedron Lett. 2003, 44,
1039.
(10) Related hindered amines (3,3,5,5-tetramethyl morpholin-2-
ones) have been shown to coordinate to palladium and undergo
C–H activation processes. See ref. 4.
3j
3b
3e
3f
<1%
3k
3l
3m
Substrate
Hydrolysisa
<1% <1%
<1%
<1%
<1%
3%
(11) For substrate 3e, degradation was observed under the reaction
conditions.
CN
NO2
(12) Compound 3k has been prepared by Lai (see ref. 7a,b) and 3l
has been prepared by author TAA using the Bargellini reaction
in 47% yield (unpublished results).
Cl
N
N
Cl
N
R1
=
N
N
(13) Synthesis of N1-(2,4-Dimethoxybenzyl)-2-methylpropane-
1,2-diamine (1c)
3a
3c
3d
32%
3g
29%
3h
32%
3i
Substrate
AcOH (0.260 mL, 4.54 mmol) was added to 2-methylpropane-
1,2-diamine (0.595 mL, 5.67 mmol) and 2,4-dimethoxybenzal-
dehyde (943 mg, 5.67 mmol) in MeOH (20 mL) at r.t. under
nitrogen. The resulting slurry turns yellow rapidly (CAUTION:
exotherm). The reaction mixture was stirred at r.t. for 1 h. The
reaction mixture was then diluted with MeOH (20 mL), NaBH4
(429 mg, 11.34 mmol) was added portionwise, and the reaction
mixture was stirred at r.t. for 1 h (CAUTION: gas evolution). The
solvent was removed under reduced pressure, and the white
residue was treated with H2O (20 mL) and extracted with CH2Cl2
(2 × 30 mL). The combined organic layers were dried (MgSO4),
filtered, and the solvent removed under reduced pressure to
give a 4:1 mixture of alkylation regioisomers. For characterisa-
tion, the crude yellow oil obtained was purified by flash silica
chromatography, elution gradient 0–10% 7 N NH3 in MeOH in
CH2Cl2. Pure fractions were evaporated to dryness to afford the
product as a 9:1 mixture of regioisomers in favor of 1c (1104
mg, 82%) as a colourless oil. Rf = 0.31 (CH2Cl2–7N NH3 in MeOH =
9:1). 1H NMR (400 MHz, CDCl3): δ = 7.14 (1 H, d, J = 8.0 Hz),
6.47–6.40 (2 H, m), 3.81 (3 H, s), 3.80 (3 H, s), 3.75 (2 H, s), 2.40
(2 H, s), 1.43 (3 H, s), 1.07 (6 H, s). 13C NMR (101 MHz, CDCl3): δ
= 160.1, 158.8, 130.3, 121.6, 103.9, 98.8, 61.7, 55.5, 55.5, 50.0,
49.9, 28.9 (2 C). IR: 3347, 2959, 2835, 1613, 1589, 1506, 1464,
Hydrolysisa
>90%
48%
18%
Scheme 5 Evaluation of the hydrolytic stability of 3a–m under basic
phase-transfer conditions. a Determined by UV analysis at 254 nm of
the mol fraction of hydrolysed material vs. the sum of parent and hy-
drolysed materials.
Acknowledgment
The authors would like to acknowledge the AstraZeneca postdoc pro-
gram for funding, as well as Becky Burton, Paul Davey, and Eva Lenz
(AstraZeneca) for analytical support.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588903.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
References and Notes
1439, 1419, 1372, 1289, 1260, 1208, 1156, 1131, 1038 cm–1
.
(1) (a) Patel, R. V.; Won Park, S. Mini-Rev. Med. Chem. 2013, 13,
1579. (b) Nakhla, J. S.; Wolfe, J. P. Org. Lett. 2007, 9, 3279.
(2) (a) Zhou, Z.; Liu, L. Curr. Org. 2014, 18, 459. (b) Ciriminna, R.;
Pagliaro, M. Org. Process Res. Dev. 2010, 14, 245. (c) Schoening,
K.-U. Chim. Oggi 2010, 28, 18. (d) Schoening, K.-U. Chim. Oggi
2010, 28, 18. (e) Schoening, K.-U. Chim. Oggi 2010, 28, 12.
(f) Schoening, K.-U. Chim. Oggi 2010, 28, 15. (g) Yoshida, E. Poly-
mers 2012, 4, 1125.
(3) Francavilla, C.; Turtle, E. D.; Kim, B.; O’Mahony, D. J. R.; Shiau, T.
P.; Low, E.; Alvarez, N. J.; Celeri, C. E.; D’Lima, L.; Friedman, L. C.;
Ruado, F. S.; Xu, P.; Zuck, M. E.; Anderson, M. B.; Najafi, R.; Jain,
R. K. Bioorg. Med. Chem. Lett. 2011, 21, 3029.
HRMS (TOF ES+): m/z calcd for C13H23N2O2 [M + H]+: 239.17540;
found: 239.17560.
(14) Synthesis of 1-(2,4-Dimethoxybenzyl)-3,3,5,5-tetrameth-
ylpiperazin-2-one (3b)
50% aq. NaOH (1.908 mL, 36.14 mmol) was added dropwise to
1,1,1-trichloro-2-methylpropan-2-ol (2.70 g, 14.46 mmol), 1c
(2.36 g, 7.23 mmol), and N-benzyl-N,N-triethylammonium
chloride (0.165 g, 0.72 mmol) in CH2Cl2 (70 mL) cooled to 0 °C.
The resulting mixture was stirred at 0 °C and left to warm to r.t.
over 20 h. The reaction mixture was treated with H2O (50 mL)
until any solid had dissolved. The organic layer was separated,
and the aqueous layer was extracted with CH2Cl2 (2 × 50 mL).
The combined organic layers were dried (MgSO4), filtered, and
concentrated under reduced pressure to give a pale yellow oil.
The crude product was purified by flash silica chromatography,
elution gradient 50–100% EtOAc in heptane, monitored at 280
(4) McNally, A.; Haffemayer, B.; Collins, B. S. L.; Gaunt, M. J. Nature
2014, 510, 129.
(5) (a) Bargellini, G. Gazz. Chim. Ital. 1906, 36, 329. For a recent
review, see: (b) Snowden, T. S. ARKIVOC 2012, (ii), 24.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

E
T. A. Alanine et al.
Letter
Synlett
nm. Pure fractions were evaporated to dryness to afford 3b
(1.510 g, 68%) as a viscous pale yellow oil; Rf = 0.12 (EtOAc). 1H
NMR (400 MHz, CDCl3): δ = 7.20 (1 H, d, J = 8.4 Hz), 6.49–6.39 (2
H, m), 4.58 (2 H, s), 3.80 (3 H, s), 3.79 (3 H, s), 3.09 (2 H, s), 1.39
(6 H, s), 1.35 (1 H, br s), 1.09 (6 H, s). 13C (101 MHz, CDCl3): δ =
173.8, 160.5, 158.9, 131.4, 117.9, 104.5, 98.6, 58.9, 55.6, 55.5,
55.5, 48.9, 45.2, 30.6 (2 C), 27.8 (2 C). IR (): 3473, 1614, 1505,
1463, 1288, 1265, 1208, 1158, 1119, 1038 cm–1. HRMS (TOF
ES+): m/z calcd for C17H27N2O3 [M + H]+: 307.20162; found:
307.20157.
(16) Representative Synthesis of 3,3,5,5-Tetramethyl-1-(pyridin-
3-yl)piperazin-2-one (3a)
1,10-Phenanthroline (10.97 mg, 0.06 mmol) was added to 3-
iodopyridine (94 mg, 0.46 mmol), 5 (p-TsOH salt, 100 mg, 0.30
mmol), CuI (11.60 mg, 0.06 mmol), and K3PO4 (323 mg, 1.52
mmol) in DMF (3 mL) at r.t. under nitrogen. The resulting
mixture was stirred at 110 °C for 1 d. The reaction mixture was
filtered through a pad of Celite®, and the filter cake was washed
with EtOAc (3 × 5 mL). The filtrate was concentrated to dryness
under reduced pressure to give a yellow residue which was
purified by flash silica chromatography, elution gradient 0–10%
MeOH in CH2Cl2. Pure fractions were evaporated to dryness to
afford 3a (49 mg, 68%) as an amorphous waxy yellow solid. Rf =
0.41 (CH2Cl2–MeOH = 9:1). 1H NMR (400 MHz, CDCl3): δ = 8.56
(1 H, d, J = 2.6 Hz), 8.48 (1 H, dd, J = 1.5, 4.8 Hz), 7.69 (1 H, ddd,
J = 1.5, 2.6, 8.2 Hz), 7.32 (1 H, ddd, J = 0.7, 4.8, 8.2 Hz), 3.64 (2 H,
s), 1.47 (7 H, s), 1.31 (6 H, s). N–H signal appeared under the
methyl signal at δ = 1.47 ppm. 13C NMR (101 MHz, CDCl3): δ =
174.4, 147.5, 146.8, 140.0, 133.3, 123.6, 62.5, 56.1, 49.7, 30.7 (2
C), 27.9 (2 C). IR (): 3357, 3057, 2969, 2928, 1669, 1587, 1572,
1467, 1434, 1402, 1347, 1302, 1283, 1246, 1206, 1173, 1151,
1110 cm–1. HRMS (TOF ES+): m/z calcd for C13H19N3O [M + H]+:
234.16009; found: 234.15987.
(15) Synthesis of 2,2,6,6-Tetramethyl-3-oxopiperazin-1-ium 4-
Methylbenzenesulfonate (5, p-TsOH Salt)
Compound 3b (2.37 g, 7.73 mmol) was dissolved in toluene (23
mL) at r.t. p-TsOH (3.24 g, 17.02 mmol) was then added, and the
resulting solution was stirred at 120 °C for 2.5 h. The reaction
was quenched with MeOH. The purple residue was triturated
with CH2Cl2 and filtered to give 5 (p-TsOH salt, 2.388 g, 94%) as
an amorphous white powder. 1H NMR (400 MHz, DMSO-d6): δ =
9.00 (2 H, br s), 8.31 (1 H, br s), 7.50 (2 H, d, J = 8.1 Hz), 7.13 (2 H,
d, J = 7.8 Hz), 3.29 (2 H, d, J = 3.2 Hz), 2.29 (3 H, s), 1.51 (6 H, s),
1.40 (6 H, s). 13C NMR (126 MHz, DMSO-d6): δ = 168.5, 145.6,
137.7, 128.1, 125.5, 57.8, 54.3, 48.1, 26.2, 22.9 (2 C), 20.8 (2 C).
IR: 3276, 1688, 1610, 1585, 1507, 1463, 1395, 1343, 1294, 1213,
101, 1185, 1165, 1094, 1034 cm–1. HRMS (TOF ES+): m/z calcd
for C8H17N2O [M + H]+: 157.13354; found: 157.13342.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E