Preparation of Substituted Tetrahydro-1-benzazepines by Lithiation-Trapping

Article abstract of DOI:10.1002/ejoc.201800868

The tetrahydro-1-benzazepine or benzo[b]azepine ring system is found in a number of drug molecules although methods to access 2,2-disubstituted derivatives are rare. Here we report the preparation of N-tert-butoxycarbonyl-2-phenyltetrahydro-1-benzazepine followed by lithiation and trapping with electrophiles. The metallation reaction was optimized by using React-IR spectroscopy, and VT-NMR spectroscopy allowed the determination of the rate of rotation of the Boc group (approximate ΔG^? 63 kJ/mol at –50 °C). The resulting organolithium was quenched to give either 2,2-disubstituted products or, with certain electrophiles, the ortho-substituted products, presumably through an η³-coordinated benzyllithium intermediate. The chemistry was shown to be amenable to extension to the 7-methoxy analog. Removal of the Boc group from the nitrogen atom led to amine products.

Full text of DOI:10.1002/ejoc.201800868

A Journal of
Accepted Article
Title: Preparation of substituted tetrahydro-1-benzazepines by
lithiation-trapping
Authors: Tahani Aeyad, Callum Jones, and Iain Coldham
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800868
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800868
Supported by

European Journal of Organic Chemistry
10.1002/ejoc.201800868
FULL PAPER
Preparation of substituted tetrahydro-1-benzazepines by
lithiation–trapping
[
a]
[a]
[a]
Tahani Aeyad, Callum G. Jones, and Iain Coldham*
Abstract: The tetrahydro-1-benzazepine or benzo[b]azepine ring
system is found in a number of drug molecules although methods to
HO
access 2,2-disubstituted derivatives are rare. Here we report the
Cl
preparation
of
N-tert-butoxycarbonyl-2-phenyltetrahydro-1-
benzazepine followed by lithiation and trapping with electrophiles.
The metallation reaction was optimized by using React-IR
spectroscopy, and VT-NMR spectroscopy allowed the determination
N
N
O
O
‡
of the rate of rotation of the Boc group (approximate G 63 kJ/mol
at –50 °C). The resulting organolithium was quenched to give either
O
H
N
N
N
2
,2-disubstituted products or, with certain electrophiles, the ortho-
H
3
substituted products, presumably through an  -coordinated
benzyllithium intermediate. The chemistry was shown to be
amenable to extension to the 7-methoxy analog. Removal of the Boc
group from the nitrogen atom led to amine products.
O
CONMe2
1
2
Figure 1. Biologically active 1-benzazepines.
Results and Discussion
Introduction
The tetrahydro-1-benzazepine compound 6 was prepared by the
addition of phenylmagnesium bromide to the benzotriazole 5
The tetrahydro-1-benzazepine ring system is found in a number
of compounds with biological activity and has potential as a
building block for drug discovery. Some examples of 1-
(
Scheme 1). The benzotriazole
commercially available lactam 3 by Boc protection to give lactam
, partial reduction with iBu AlH (DIBAL-H) and reaction with
5 was made from the
1
benzazepines include the vasopressin receptor antagonist
tolvaptan (1) and the anti-diuretic fedovapagon (2) (Fig. 1).2
Many routes have been developed for the synthesis of
4
2
benzotriazole, following literature precedent on
a related
6,10
lactam.
The partial reduction of lactam 4 provided a mixture of
3
tetrahydro-1-benzazepines, although the formation of 2,2-
the alcohol and the ring-opened aldehyde product, but this
mixture was amenable to conversion directly to the
benzotriazole compound 5 in good overall yield (75%). The
Grignard addition step was performed in Et O with some THF to
2
aid solubility. Reaction in neat THF resulted in a lower yield of
the product 6 and the reaction was best conducted in a mixture
2
of Et O–THF. The structure of the tetrahydro-1-benzazepine 6
was verified by single crystal X-ray analysis (see SI). This
showed a torsion angle between the fused aromatic ring and the
N–CO bond of 67°, suggesting poor overlap between the
nitrogen p-orbital and this aromatic ring.
4
disubstituted derivatives is relatively rare. Our research group
has reported chemistry to prepare 2,2-disubstituted
tetrahydroquinolines,5 azepanes,6 and other alpha-amino
substituted compounds7 by using a lithiation–trapping protocol.
We were therefore interested to extend this chemistry to 1-
benzazepines. Although lithiation next to a nitrogen atom
followed by electrophilic quench is well-known for pyrrolidines
8
and piperidines, there is only one example, as far as we are
aware, of this type of reaction with a tetrahydro-1-benzazepine,
in which Meyers and Milot prepared a small selection of mono-
substituted products.9 The most popular directing group on the
nitrogen atom is the N-tert-butoxycarbonyl (N-Boc) group which
promotes lithiation alpha to the nitrogen atom and we therefore
needed access to N-Boc-2-aryltetrahydro-1-benzazepines.
1
. DIBAL-H
THF, –78 °C
Boc O
2
THF, DMAP
room temp.
2. Benzotriazole
PhMe, 110 °C
N
H
N
O
O
Boc
4
3
93%
75%
[
a]
T. Aeyad, C. G. Jones, I. Coldham*
Department of Chemistry
PhMgBr
University of Sheffield
Brook Hill, Sheffield S3 7HF
UK
Et O–THF (9:1)
room temp.
N
2
N
Bt
Ph
Boc
Boc
E-mail: i.coldham@sheffield.ac.uk
https://www.sheffield.ac.uk/chemistry/staff/profiles/iain_coldham
5
70%
6
Supporting information for this article is available on the WWW
under https://doi.org/10.1002/ejoc.201800868.
Scheme 1. Preparation of the carbamate 6 (Bt = benzotriazolyl).
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European Journal of Organic Chemistry
10.1002/ejoc.201800868
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The lithiation of the 1-benzazepine 6 was successful by using
nBuLi in THF. The optimum temperature and time was verified
by in situ ReactIR spectroscopy (Fig. 2). The lithiation was slow
at –78 °C but at –50 °C the reaction was complete in a few
minutes, as judged by the formation of a new carbonyl stretch,
ν
C=O at 1644 cm–1 for the lithiated compound.
Figure 3. 1H NMR spectra of 1-benzazepine 6 in D
.30–2.60 ppm.
6
-DMSO showing region
5
The barrier to rotation of the Boc group is about 63 kJ/mol at –
0 °C and this is lower than that for the related azepane
approximate G‡ 71 kJ/mol at –50 °C).5 The faster rate of
5
(
rotation is likely due to at least partial conjugation of the nitrogen
lone pair with the aromatic ring, thereby reducing the interaction
with the carbonyl group. However this conjugation will be
tempered by the lack of planarity and the value of 63 kJ/mol is
significantly higher than that for the corresponding
‡
tetrahydroquinoline (approximate G 47 kJ/mol at –50 °C)
where the torsion angle is lower.5
Figure 2. ReactIR spectra for lithiation of 6 with nBuLi added after about 12
min in THF at –50 °C; νC=O at 1702 cm–1 for 6 and νC=O at 1644 cm–1 for
lithiated 6 (Time in h:min:sec).
Using the data above, we treated the 1-benzazepine 6 with
nBuLi (1.2 equivalents) in THF at –50 °C. After 10 min, the
organolithium intermediate was trapped with a range of different
electrophiles to give the products 7a–f (Scheme 2). The
products 7a–f were formed with good yields in which the
electrophile adds at C-2 of the benzazepine ring. The reaction
was successful for tributyltin chloride, alkyl and allyl halides, and
for carbonyl electrophiles. In the latter case the intermediate
alkoxide cyclizes on to the Boc group to give the cyclic
carbamate. With benzaldehyde as the electrophile, the trapping
The slow lithation at –78 °C is due to the slow rotation around
the N–CO bond combined with the requirement for the carbonyl
group to be directed towards the benzylic proton for lithiation to
1
1
occur. 1H NMR spectroscopy indicated that the two rotamers
were present in about 1.2:1 ratio and variable temperature NMR
spectroscopy was performed (Fig. 3). By using line shape
analysis, the activation parameters can be estimated and this
‡
‡
led to approximate values of H 56 kJ/mol and S –32 J/K·mol. occurred stereoselectively to give the product 7f as the major
These results, albeit in DMSO as the solvent (to allow for
elevated temperatures to observe coalescence), give a half-life
for rotation of about 2 h at –78 °C but only about 80 s at –50 °C.
These data match those found using in situ ReactIR
spectroscopy and verify that the best conditions for lithiation use
the higher temperature.
(separable) isomer with the phenyl groups trans to each other.
This was verified by single crystal X-ray analysis (Fig. 4).
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European Journal of Organic Chemistry
10.1002/ejoc.201800868
FULL PAPER
related tetrahydroquinoline system suggest that coordination of
a cyanoformate to the lithium atom alters the structure of the
organolithium towards the 3-coordination mode.5 This is
presumably also the case here with the 1-benzazepine not only
with cyanoformates but also with certain other electrophiles
n-BuLi
R
Ph
THF, –50 °C
N
N
Ph
10 min
Boc
Boc
then R–X
6
7a–f
(
2
MeOCOCl and PhSSO Ph). After reaction at the ortho position,
rearomatization would provide the products 8a–b. In contrast,
alkyl halides and aldehydes/ketones react at C-2 (Scheme 2)
suggesting that the organolithium is located predominantly on C-
SnBu3
Ph
Me
Ph
N
N
Boc
Boc
2
and that these electrophiles interact differently (in comparison
7
5% 7a
60% 7b
R–X = MeI
with, for example, formates) during reaction with the
organolithium species.
R–X = Bu SnCl
3
Br
n-BuLi
N
R’
N
Ph
Ph
THF, –50 °C
Boc
N
N
Boc
Ph
10 min
Boc
6
Boc
8a–b
8
5% 7c
R–X = allyl bromide
78% 7d
R–X = Br(CH ) Br
then R’–X
2
4
Ph
N
Ph
Ph
CO Me
SPh
2
N
N
N
O
O
O
O
Boc
Boc
7
0% 7e
79% 7f dr 15:1
R–X = PhCHO
8a
85% 8b
R–X = acetone
R’–X = MeOCOCN 68%
R’–X = MeOCOCl 63%
R’–X = PhSSO Ph
2
Scheme 2. Lithiation–trapping to give the carbamates 7a–f.
Scheme 3. Lithiation–trapping to give the carbamates 8a–b.
To illustrate the relevance of the chemistry, we treated the
carbamates 7d and 8a with trifluoroacetic acid (TFA) at room
temperature in CH
2 2
Cl to give new products 9 and 10 (Scheme
4
). The secondary amine 10 was formed from carbamate 8a
Ph
Ph
although the amine product generated by removal of the Boc
group from carbamate 7d cyclized in situ with displacement of
bromide to give the tricyclic amine product 9 in high yield. Fused
tricyclic amines with an aryl group alpha to the nitrogen atom are
of interest in synthetic and medicinal chemistry and are present
in biologically active compounds such as antidepressants and N-
methyl-D-aspartate receptor antagonists.13
N
O
O
7f
Figure 4. Crystal structure of the major isomer of the carbamate 7f.
In previous work with N-Boc-2-phenylazepane and N-Boc-2-
phenyltetrahydroquinoline, we had found that lithiation followed
by addition of alkyl cyanoformate electrophiles provided the
unusual ortho-substituted products.5,6 We therefore tested this
with methyl cyanoformate and found the same type of switch to
the ortho-substituted product 8a (Scheme 3). The same product
TFA, CH Cl2
2
Br
Ph
room temp.
N
N
Ph
2
h
Boc
7d
88%
9
8
a was also formed by using methyl chloroformate as the
electrophile. In addition, the ortho-substituted product 8b was
formed on using the electrophile PhSSO Ph. These data,
CO Me TFA, CH2Cl2
CO Me
2
2
2
N
room temp.
N
combined with those from the ReactIR and Scheme 2, suggest
that the lithium atom in the intermediate organolithium species
2
h
Boc
H
8a
86% 10
(
typically drawn as if located at C-2 of the benzazepine with
3
coordination to the Boc carbonyl group) has  -coordination to
the phenyl group. Both  - and  -coordination of benzyllithiums
Scheme 4. Removal of the Boc group to give amines 9–10.
1
3
1
2
is known. Density functional theory calculations with the
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European Journal of Organic Chemistry
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FULL PAPER
Finally, we have demonstrated that the chemistry is amenable to Conclusions
a derivative, namely the 7-methoxy analog 13. The carbamate
1
3 was prepared from the commercially available ketone 11
A selection of substituted 2-aryltetrahydro-1-benzazepines can
be prepared by lithiation then trapping with different electrophiles.
Variable temperature NMR spectroscopy, which provides
knowledge of the rate of rotation of the Boc group, and in situ
ReactIR spectroscopy were found to be suitable methods by
which the lithiation reactions can be optimised. Alkyl halides,
tributyltin chloride, aldehydes and ketones lead to the 2,2-
disubstituted products. However, chloroformates, cyanoformates,
1
4,15
following related literature methods (Scheme 5).
Reduction
of the oxime to give the hydroxylamine 12 is reported with
sodium cyanoborohydride in acetic acid.14 We found that the
presence of acetic acid led to difficulties in isolation of
hydroxylamine 12, and it was preferable to use hydrochloric acid
instead. The hydroxylamine 12 was treated with phenyllithium to
promote loss of methoxide, rearrangement and addition of the
phenyl group.15 The lithiated secondary amine could be
protonated according to the literature but the subsequent
2
and PhSSO Ph lead to ortho substituted products. This may be
1
3
due to a change in the structure ( or  ) of the organolithium
as it reacts with/coordinates to the different electrophiles.4 The
products can be converted to amines by removal of the Boc
group.
conversion to the carbamate 13 with a base and Boc
unsatisfactory in terms of yield. However, rather than isolate the
secondary amine, direct addition of Boc O to the lithiated
2
O was
2
intermediate resulted in a good yield for in situ one-pot formation
of the carbamate 13.
In the same way as the 1-benzazepine 6, treatment of the 1-
benzazepine 13 with nBuLi in THF at –50 °C for 10 min was
followed by addition of a selection of electrophiles (Scheme 6).
We were pleased to find that this gave good yields of the
substituted products 14–16. The reactivity matched that of the 1-
benzazepine 6, where addition of acetone gave the cyclic
carbamate (15) and addition of ethyl chloroformate resulted in
the ortho-substituted product (16).
Experimental Section
General details: Reagents were obtained from commercial suppliers and
were used without further purification except for methyl chloroformate,
allyl bromide, benzaldehyde, and 1,4-dibromobutane that were used after
distillation; nBuLi was titrated before use. Solvents were obtained from a
Grubbs dry solvent system. Thin layer chromatography was performed
on Merck silica gel 60F254 plates and visualised by UV irradiation at 254
nm or by staining with an alkaline KMnO
chromatography was performed using DAVISIL or Geduran silica gel (40-
3 micron mesh). Melting points were recorded on a Gallenkamp hot
4
dip. Flash column
6
1
. NH OMe·HCl
2
MeO
MeO
stage and were uncorrected. InfraRed spectra were recorded on a Perkin
Elmer Spectrum RX Fourier Transform – IR System and only selected
peaks are reported. 1H NMR spectra were recorded on a Bruker AC400
(400 MHz) instrument. Chemical shifts are reported in ppm with respect
to the residual solvent peaks, with multiplicities given as s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet, br = broad. Coupling
constants (J values) are quoted to the nearest 0.5 Hz with values in Hertz
pyridine, MeOH 91%
2
. NaBH CN, MeOH
3
then HCl
63%
O
NHOMe
11
12
3
equiv. PhLi
2
MeO
Et O, 0 °C
(
Hz). 13C NMR spectra were recorded on the above instrument at 100
then Boc O
MHz. Low and high resolution (accurate mass) mass spectra were
recorded on a Walters LCT instrument for Electro–Spray (ES). ReactIR
infrared spectroscopic monitoring was performed on a Mettler-Toledo
ReactIR iC 4000 spectrometer equipped with a diamond-tipped (DiComp)
probe.
2
N
Ph
Boc
77%
13
Scheme 5. Preparation of the carbamate 13.
tert-Butyl 2,3,4,5-Tetrahydro-2-oxobenzo[b]azepine-1-carboxylate 4:
Di-tert-butyl dicarbonate (4.7 g, 20 mmol) in dry THF (15 mL) was added
to commercially available 2,3,4,5-tetrahydro-1H-1-benzazepin-2-one 3
MeO
MeO
n-BuLi
(3.0 g, 19 mmol) and 4-(N,N-dimethylamino)pyridine (2.5 g, 20 mmol) in
THF, –50 °C
10 min
then R–X
dry THF (50 mL) at room temperature. After 3 h, the solvent was
evaporated and EtOAc (50 mL) was added. The mixture was washed
with aqueous HCl (3 × 50 mL, 0.5 M), saturated brine solution (3 × 25 mL)
N
Boc
3
N
SnBu3
Ph
Ph
Boc
65% 14
R–X = Bu SnCl
1
and saturated NaHCO
MgSO ) and the solvent was evaporated. Purification by flash silica
chromatography, eluting with CH Cl –MeOH (95:5), gave the carbamate
(4.5 g, 93%) as an amorphous solid; m.p. 110–112 ºC; R
3
solution (3 × 25 mL). The organic layer was dried
3
(
4
MeO
MeO
2
2
4
f
0.26 [petrol–
CO Et
EtOAc (70:30)]; FT-IR νmax (film)/cm–1 2980, 2930, 2860, 1765, 1715; H
1
2
Ph
N
N
NMR (400 MHz, CDCl
3
) δ = 7.39–7.20 (3H, m, 3 × CH), 7.19–7.05 (1H,
), 2.28 (2H, t, J = 7.0 Hz, CH ), 2.19–
), 1.47 (9H, s, t-Bu); 13C NMR (100 MHz, CDCl
) δ =
Boc
O
O
m, CH), 2.81 (2H, t, J = 7.0 Hz, CH
2
2
2
1
2
2
.05 (2H, m, CH
2
3
7
8% 15
60% 16
R–X = EtOCOCl
72.6, 151.4, 138.8, 135.5, 129.0, 127.8, 127.1, 126.1, 83.5, 34.7, 29.3,
R–X = acetone
+
requires MH+,
7.8, 27.5; HRMS (ES) Found: MH , 262.1443. C15
H
20NO
3
+
62.1438; LRMS m/z (ES) 262 (5%, MH ), 206 (100).
Scheme 6. Lithiation–trapping of the carbamate 13.
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European Journal of Organic Chemistry
10.1002/ejoc.201800868
FULL PAPER
tert-Butyl-2-(1H-Benzo[d][1,2,3]triazol-1-yl)-2,3,4,5-
127.2, 127.1, 126.9, 126.6, 126.5, 126.4, 126.0, 80.5, 79.8, 61.0, 59.4,
32.1, 31.2, 29.7, 29.5, 28.3, 28.2, 23.7, 23.0; HRMS (ES) Found: MNa ,
+
tetrahydrobenzo[b]azepine-1-carboxylate 5: DIBAL-H (21.4 mL, 21.4
mmol, 1 M in cyclohexane) was added dropwise to the carbamate 4 (4.0
g, 15 mmol) in dry THF (50 mL) at –78 ºC. After 1 h, the mixture was
allowed to warm to room temperature over a further 1 h. Saturated
aqueous potassium acetate solution (20 mL) was added slowly. The
solids were removed by filtration and were washed with EtOAc (3 × 25
mL). The organic layers were combined, washed with saturated brine
+
346.1779. C21
(5%, MNa ), 268 (100%).
H
25NO
2
Na requires MNa , 346.1778; LRMS m/z (ES) 346
+
tert-Butyl
2-(Tributylstannyl)-2,3,4,5-tetrahydro-2-
phenylbenzo[b]azepine-1-carboxylate 7a: nBuLi (0.15 mL, 0.37 mmol,
.4 M in hexane) was added to the carbamate 6 (100 mg, 0.31 mmol) in
2
solution (4 × 25 mL), dried (MgSO
Purification by flash silica chromatography, eluting with CH
(
4
), and the solvent was evaporated.
Cl –MeOH
95:5), gave a mixture of the 2-hydroxy compound and the aldehyde (3.6
dry THF (2 mL) at –50 ºC under nitrogen. After 10 minutes, tributyltin
chloride (0.25 mL, 0.93 mmol) was added. The mixture was allowed to
warm slowly to room temperature and MeOH (1 mL) was added. The
solvent was evaporated and the mixture was absorbed onto silica then
was purified by flash column chromatography on silica gel, eluting with
petrol–EtOAc (99:1), to give the carbamate 7a (142 mg, 75%) as an oil;
2
2
f
g, 89%) (ratio 60:40) as an oil; R 0.50 (alcohol), 0.75 (aldehyde)
2 2
Cl
–EtOAc (90:10)]; FT-IR νmax (film)/cm–1 3450, 3360, 2970, 2980,
[
2
CH
940, 2870, 1710, 1680; H NMR (400 MHz, CDCl
δ = 9.82 (0.4H, t, J = 1.0 Hz, CHO), 7.82 (0.4H, d, J = 8.0 Hz, CH), 7.25–
1
3
, mixture of isomers)
0.75 [petrol–EtOAc (80:20)]; FT-IR νmax (film)/cm–1 2955, 2920, 2860,
R
f
7
6
.19 (1.6H, m, CH), 7.17–7.11 (1.6H, m, CH), 7.04–7.01 (0.4H, m, CH),
.80 (0.4H, br s, NH), 5.71–5.54 (0.6H, m, CH), 3.92 (0.6H, s, OH), 2.75
1
1670; H NMR (400 MHz, CDCl
3
) δ = 7.24–6.94 (9H, m, 9 × CH), 2.99–
2.86 (1H, m, CH), 2.60 (1H, dt, J = 9.0, 4.5 Hz, CH), 2.55–2.45 (1H, m,
(
0.6H, td, J = 13.0, 7.0 Hz, CH), 2.62–2.54 (2.4H, m, 4 × CH), 1.95–1.77
2.2H, m, CH), 1.55 (3.7H, s, t-Bu), 1.54–1.52 (0.8H, m, CH), 1.40 (5.3H,
CH), 1.92–1.82 (2H, m, 2 × CH), 1.47–1.19 (22H, m, t-Bu, CH, 3 ×
(
CH
2
CH
2
), 0.87 (9H, t, J = 7.0 Hz, 3 × CH
3 2
), 0.83–0.65 (6H, m, 3 × CH );
s, t-Bu); 13C NMR (100 MHz, CDCl
, mixture of isomers) δ = 202.4, 155.5,
53.6, 137.1, 136.5, 136.1, 131.0, 129.4, 129.2, 128.9, 128.3, 127.1,
3
13
C NMR (100 MHz, CDCl
3
) δ = 156.8, 139.6, 138.4, 131.3, 130.3, 128.2,
1
1
2
1
27.8, 126.8, 126.0, 125.0, 123.8, 79.8, 61.8, 35.2, 32.5, 29.1, 28.3, 27.7,
26.5, 123.9, 122.2, 80.8, 80.3, 78.9, 43.0, 30.6, 29.7, 29.4, 28.4, 28.3,
+
120
22.6, 13.7, 13.5; HRMS (ES) Found: MNa , 636.2841. C33
H
H
51NO
51NO
2
Sn
Sn
+
2.0, 21.2; HRMS (ES) Found: MNa , 286.1417. C15
3
H21NO Na requires
+
+
118
Na requires MNa , 636.2839; Found: MNa , 634.2863. C33
Na requires MNa , 634.2860; LRMS m/z (ES) 636 (72%, MNa ), 634 (50,
MNa ), 500 (35), 498 (25), 212 (100).
2
+
+
MNa , 286.1414; LRMS m/z (ES) 286 (5%, MH ), 190 (100), 146 (85). It
was possible to separate the aldehyde from this mixture and its data are
as follows: H NMR (400 MHz, CDCl
+
+
+
1
3
) δ = 9.83 (1H, br s, CHO), 7.84 (1H,
d, J = 8.0 Hz, CH), 7.25–7.20 (1H, m, CH), 7.13 (1H, d, J = 7.0 Hz, CH),
tert-Butyl 2,3,4,5-Tetrahydro-2-methyl-2-phenylbenzo[b]azepine-1-
carboxylate 7b: nBuLi (0.15 mL, 0.37 mmol, 2.4 M in hexane) was
added to the carbamate 6 (100 mg, 0.31 mmol) in dry THF (2 mL) at –50
ºC under nitrogen. After 10 minutes, iodomethane (0.06 mL, 0.93 mmol)
was added. The mixture was allowed to warm slowly to room
temperature and MeOH (1 mL) was added. The solvent was evaporated
and the mixture was absorbed onto silica then was purified by flash
column chromatography on silica gel, eluting with petrol–EtOAc (98:2), to
7
1
.07–7.01 (1H, m, CH), 6.80 (1H, br s, NH), 2.63–2.54 (4H, m, 4 × CH),
.95–1.84 (2H, m, 2 × CH), 1.55 (9H, s, t-Bu); 13C NMR (100 MHz, CDCl
3
)
δ = 202.3, 153.5, 136.0, 131.0, 129.4, 127.1, 123.9, 122.0, 80.3, 43.0,
0.6, 28.4, 22.0. Benzotriazole (2.0 g, 17 mmol) and MgSO (0.5 g) were
3
4
added to this mixture (3.0 g, 11 mmol) in toluene (70 mL). The mixture
was heated under reflux for 18 h then was allowed to cool to room
temperature, before washing with saturated aqueous NaCO
3
solution (3
×
20 mL) and saturated brine solution (3 × 20 mL). The organic layers
give the carbamate 7b (62 mg, 60%) as an oil; R
f
0.65 [petrol–EtOAc
4
were dried (MgSO ) and the solvent was evaporated. Purification by flash
80:20)]; FT-IR νmax (film)/cm–1 2960, 2930, 2860, 1695; 1H NMR (400
(
silica chromatography, eluting with petrol–EtOAc (75:25), gave the
carbamate 5 (3.50 g, 84%), as an oil; R 0.45 [petrol–EtOAc (70:30)]; FT-
IR νmax (film)/cm–1 3025, 2970, 1690; 1H NMR (400 MHz, CDCl
) δ =
.08–7.43 (3H, m, 3 × CH), 7.42–7.02 (5H, m, 3 × CH), 6.90–6.62 (1H, m,
NCH), 3.06–2.93 (1H, m, CH), 2.83–2.68 (1H, m, CH), 2.54–1.84 (4H, m,
× CH), 1.33 (9H, s, t-Bu); 13C NMR (100 MHz, CDCl
, the C=O could
not be observed) δ = 143.9, 137.6, 136.8, 136.5, 128.7, 128.2, 127.3,
MHz, CDCl , rotamers) δ = 7.56–7.15 (9H, m, 9 × CH), 3.20–2.87 (1H, m,
CH), 2.72–2.60 (1H, m, CH), 2.12–1.89 (1H, m, CH), 1.81–1.43 (3H, m, 3
3
f
3
); 13C NMR (100 MHz, CDCl
CH), 1.31–1.02 (12H, m, t-Bu and CH
rotamers) δ = 156.2, 154.7, 145.1, 145.0, 138.9, 138.7, 137.2, 136.7,
×
3
3
,
8
1
1
2
C
29.9, 129.5, 128.9, 128.2, 128.0, 127.2, 126.9, 126.7, 126.5, 126.3,
4
3
26.0, 125.9, 125.6, 124.7, 80.5, 79.8, 61.4, 61.0, 32.2, 31.2, 30.3, 29.7,
+
9.6, 28.3, 28.2, 28.0, 23.0, 21.6; HRMS (ES) Found: MH , 338.2112.
1
26.1, 123.9, 119.7, 118.5, 110.6, 79.0, 66.8, 29.9, 29.6, 29.1, 28.1;
+
+
22
H
28NO
2
requires MH , 338.2115; LRMS m/z (ES) 338 (5%, MH ), 282
+
Na, requires MNa+,
HRMS (ES) Found: MNa , 387.1793. C21
H N O
24 4 2
(100).
+
387.1791; LRMS m/z (ES) 387 (15% MNa ), 190 (28), 146 (100).
tert-Butyl
2-Allyl-2,3,4,5-Tetrahydro-2-phenylbenzo[b]azepine-1-
tert-Butyl 2,3,4,5-Tetrahydro-2-phenylbenzo[b]azepine-1-carboxylate
: Phenylmagnesium bromide solution (14.6 mL, 44 mmol, 3 M in Et O)
was added dropwise to the carbamate 5 (4.0 g, 11 mmol) in dry Et O–
THF (100 mL, 9:1) at 0 °C. After 20 h, the mixture was allowed to warm
slowly to room temperature, then a saturated solution of NH Cl (10 mL)
carboxylate 7c: nBuLi (0.15 mL, 0.37 mmol, 2.4 M in hexane) was
added to the carbamate 6 (100 mg, 0.31 mmol) in dry THF (2 mL) at –50
ºC under nitrogen. After 10 minutes, allyl bromide (0.08 mL, 0.93 mmol)
was added. The mixture was allowed to warm slowly to room
temperature and MeOH (1 mL) was added. The solvent was evaporated
and the mixture was absorbed onto silica then was purified by flash
column chromatography on silica gel, eluting with petrol–EtOAc (98:2), to
6
2
2
4
was added and was extracted with ether (3 × 25 mL). The combined
organic layers were washed with saturated brine solution (4 × 25 mL),
dried (MgSO
silica chromatography, eluting with petrol–EtOAc (95:5), gave the
carbamate 6 (2.48 g, 70%) as needles; m.p. 110–112 ºC; R 0.65 [petrol–
EtOAc (80:20)]; FT-IR νmax (film)/cm–1 2980, 2945, 2855, 1690; 1H NMR
400 MHz, CDCl , rotamers) δ = 7.54–7.19 (9H, m, 9 × CH), 5.17 (0.55H,
br d, J = 12.0 Hz, NCH), 4.94 (0.45H, br d, J = 12.0 Hz, NCH), 3.08–2.89
1H, m, CH), 2.65 (1H, dd, J = 13.0, 8.0 Hz, CH), 2.04–1.90 (1H, m, CH),
4
), and the solvent was evaporated. Purification by flash
give the carbamate 7c (94 mg, 85%) as an oil; R
f
0.68 [petrol–EtOAc
70:30)]; FT-IR νmax (film)/cm-1 2965, 2925, 2850, 1695; 1H NMR (400
(
f
MHz, CDCl , rotamers) δ = 7.77–7.53 (1H, m, CH), 7.41–7.19 (8H, m, 8 ×
CH), 5.36–5.00 (1H, m, =CH), 4.99–4.58 (2H, m, =CH ), 3.03–2.83 (1H,
m, CH), 2.73–2.62 (1H, m, CH), 2.54–2.12 (3H, m, 3 × CH), 2.03–1.86
1H, m, CH), 1.74–1.65 (1H, m, CH), 1.31 (3H, s, t-Bu), 1.12 (6H, s, t-Bu),
3
2
(
3
(
(
.99–0.88 (1H, m, CH); 13C NMR (100 MHz, CDCl
41.3, 134.7, 130.7, 129.1, 128.3, 127.5, 127.2, 126.6, 125.8, 125.4,
18.2, 80.5, 68.1, 29.7, 27.9, 23.6, 23.1, 22.1; HRMS (ES) Found: MH ,
0
1
1
3
) δ = 155.5, 143.1,
1
.84–1.62 (2H, m, 2 × CH), 1.58–1.42 (1H, m, CH), 1.31 (9H, s, t-Bu);
, rotamers) δ = 154.9, 154.6, 146.5, 144.9,
38.9, 138.8, 137.3, 137.2, 130.0, 129.8, 128.5, 128.4, 128.2, 128.1,
1
3C NMR (100 MHz, CDCl
3
+
1
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201800868
FULL PAPER
+
3
64.2272. C24
H
30NO
2
requires MH , 364.2271; LRMS m/z (ES) 364 (5%,
tert-Butyl
2-(2-(Methoxycarbonyl)phenyl)-2,3,4,5-
+
MH ), 308 (100).
tetrahydrobenzo[b]azepine-1-carboxylate 8a: nBuLi (0.15 mL, 0.37
mmol, 2.4 M in hexane) was added to the carbamate 6 (100 mg, 0.31
mmol) in dry THF (2 mL) at –50 ºC under nitrogen. After 10 minutes,
methyl cyanoformate (0.07 mL, 0.91 mmol) was added. The mixture was
allowed to warm slowly to room temperature and MeOH (1 mL) was
added. The solvent was evaporated and the mixture was absorbed onto
silica then was purified by flash column chromatography on silica gel,
eluting with petrol–EtOAc (95:5), to give the carbamate 8a (71 mg, 68%)
tert-Butyl
2-(4-Bromobutyl)-2,3,4,5-tetrahydro-2-
phenylbenzo[b]azepine-1-carboxylate 7d: nBuLi (0.15 mL, 0.37 mmol,
.4 M in hexane) was added to the carbamate 6 (100 mg, 0.31 mmol) in
dry THF (2 mL) at –50 ºC under nitrogen. After 10 minutes, 1,4-
dibromobutane (0.11 mL, 0.93 mmol) was added. The mixture was
allowed to warm slowly to room temperature and MeOH (1 mL) was
added. The solvent was evaporated and the mixture was absorbed onto
silica then was purified by flash column chromatography on silica gel,
eluting with petrol–EtOAc (80:20), to give the carbamate 7d (109 mg,
0.34 [petrol–EtOAc (80:20)]; FT-IR νmax (film)/cm-1
950, 2925, 2860, 1700; H NMR (400 MHz, CDCl
m, 9 × CH), 3.17–3.05 (2H, m, 2 × CH), 2.89–2.77 (1H, m, CH), 2.74–
.65 (1H, m, CH), 2.62–2.34 (2H, m, 2 × CH), 2.06–1.90 (1H, m, CH),
2
as an oil; R
f
0.43 [petrol–EtOAc (60:40)]; FT-IR νmax (film)/cm-1 2975,
1
2940, 2860, 1720, 1695; H NMR (400 MHz, CDCl
3
, rotamer ratio 7:3) δ
=
7.92 (1H, d, J = 8.0 Hz, CH), 7.64–7.43 (3H, m, 3 × CH), 7.42–7.36 (1H,
m, CH), 7.35–7.20 (3H, m, 3 × CH), 5.96 (0.3H, d, J = 12.0 Hz, CH), 5.81
(0.7H, d, J = 12.0 Hz, CH), 3.95 (3H, s, CH ), 3.07–2.90 (1H, m, CH),
.67 (1H, dd, J = 13.0, 7.0 Hz, CH), 2.16–2.03 (1H, m, CH), 1.96–1.87
1H, m, CH), 1.70–1.59 (1H, m, CH), 1.39–1.32 (1H, m, CH), 1.28 (3H, s,
t-Bu), 1.18 (6H, s, t-Bu); 13C NMR (100 MHz, CDCl
, rotamers) δ = 167.6,
167.3, 154.7, 154.3, 150.6, 149.1, 139.7, 139.3, 137.9, 137.2, 132.5,
78%) as an oil; R
f
1
3
2
3
) δ = 7.71–7.12 (9H,
2
(
2
1
3
3
.73–1.56 (2H, m, 2 × CH), 1.54–1.43 (2H, m, 2 × CH), 1.34–1.25 (3H, m,
× CH), 1.10 (9H, s, t-Bu); 13C NMR (100 MHz, CDCl
3 2
, one CH missing)
1
1
32.1, 130.6, 130.1, 129.7, 129.4, 128.6, 128.3, 128.0, 127.5, 127.1,
26.9, 126.8, 126.4, 126.0, 125.7, 125.5, 125.3, 80.3, 80.1, 57.2, 56.6,
δ = 153.4, 141.3, 134.1, 133.7, 130.6, 129.2, 128.5, 127.5, 126.7, 125.9,
1
25.3, 80.2, 66.0, 39.7, 33.7, 33.3, 32.8, 29.7, 27.9, 22.5; HRMS (ES)
+
79
+
52.3, 52.0, 31.8, 31.6, 29.7, 29.6, 28.2, 27.9, 24.0, 23.8; HRMS (ES)
Found: MH , 382.1942. C23
(ES) 382 (100%, MH ). Alternatively, compound 8a was prepared by
addition of methyl chloroformate (0.07 mL, 0.93 mmol), which gave the
carbamate 8a (66 mg, 63%) as an oil; data as above.
Found: MNa , 480.1507. C25
Found: MNa , 482.1489. C25
LRMS m/z (ES) 482 (10%, MNa ), 480 (10, MNa ), 404 (100), 402 (100).
H
32 BrNO
2
Na requires MNa , 480.1509;
+
+
+
81
+
H28NO
4
requires MH , 382.1930; LRMS m/z
H32 BrNO
2
Na requires MNa , 482.1492;
+
+
+
,5-Dimethyl-6-phenyl-4-oxa-2-azatricyclo[8.4.0.02,6]tetradeca-
(10),11,13-trien-3-one 7e: nBuLi (0.19 mL, 0.44 mmol, 2.4 M in hexane)
5
1
tert-Butyl
phenylthio)phenyl)benzo[b]azepine-1-carboxylate 8b: nBuLi (0.15
mL, 0.37 mmol, 2.4 M in hexane) was added to the carbamate 6 (100 mg,
.31 mmol) in dry THF (2 mL) at –50 ºC under nitrogen. After 10 minutes,
2,3,4,5-Tetrahydro-2-(2-
was added to the carbamate 6 (100 mg, 0.31 mmol) in dry THF (2 mL) at
50 ºC under nitrogen. After 10 minutes, acetone (0.07 mL, 0.93 mmol)
(
–
was added. The mixture was allowed to warm slowly to room
temperature and MeOH (1 mL) was added. The solvent was evaporated
and the mixture was absorbed onto silica then was purified by flash
column chromatography on silica gel, eluting with petrol–EtOAc (95:5), to
0
S-phenyl benzenethiosulfonate (0.23 mL, 0.93 mmol) was added. The
mixture was allowed to warm slowly to room temperature and MeOH (1
mL) was added. The solvent was evaporated and the mixture was
absorbed onto silica then was purified by flash column chromatography
on silica gel, eluting with petrol–EtOAc (95:5), to give the carbamate 8b
give the carbamate 7e (66 mg, 70%) as an oil; R
(
f
0.37 [petrol–EtOAc
70:30)]; FT-IR νmax (film)/cm-1 2965, 2925, 2855, 1745; 1H NMR (400
MHz, CDCl ) δ = 7.58 (1H, d, J = 8.0 Hz, CH), 7.45–7.04 (8H, m, 8 × CH),
3
(
110 mg, 85%) as an amorphous solid; m.p. 94–96 ºC; R
EtOAc (60:40)]; FT-IR νmax (film)/cm-1 2930, 2855, 1670; 1H NMR (400
MHz, CDCl , rotamers) δ = 7.69–7.08 (13H, m, 13 × CH), 5.17 (0.5H, d, J
12.0 Hz, CH), 4.93 (0.5H, d, J = 12.0 Hz, CH), 3.10–2.88 (1H, m, CH),
f
0.42 [petrol–
2
.86–2.68 (3H, m, 3 × CH), 2.28–2.17 (1H, m, CH), 1.99–1.88 (1H, m,
); 13C
CH), 1.56 (3H, s, CH
NMR (100 MHz, CDCl
), 1.36–1.30 (1H, m, CH), 1.02 (3H, s, CH
3 3
3
3
) δ = 156.6, 139.5, 136.6, 136.5, 131.0, 130.6,
=
1
29.6, 128.3, 127.5, 127.4, 127.1, 85.1, 72.3, 36.3, 35.9, 26.2, 21.2, 21.1;
+
+
2.65 (1H, dd, J = 13.0, 8.0 Hz, CH), 2.04–1.89 (1H, m, CH), 1.83–1.62
(2H, m, 2 × CH), 1.57–1.43 (1H, m, CH), 1.30 (9H, s, t-Bu); 13C NMR
HRMS (ES) Found: MH , 308.1648. C20
LRMS m/z (ES) 330 (10%, MNa ), 308 (100, MH ).
H22NO
2
requires MH , 308.1645;
+
+
(100 MHz, CDCl
3
, rotamers) δ = 154.9, 154.7, 146.6, 145.0, 143.0, 142.7,
,
6
138.9, 138.8, 137.3, 137.2, 136.6, 135.4, 133.6, 132.2, 131.6, 131.4,
5
,6-Diphenyl-4-Oxa-2-azatricyclo[8.4.0.0² ]tetradeca-1(10),11,13-
1
1
1
2
30.4, 130.0, 129.8, 129.5, 129.3, 129.1, 129.0, 128.8, 128.5, 128.4,
28.3, 128.2, 127.9, 127.8, 127.6, 127.2, 126.9, 126.6, 126.5, 126.0,
trien-3-one 7f: nBuLi (0.15 mL, 0.37 mmol, 2.4 M in hexane) was added
to the carbamate 6 (100 mg, 0.31 mmol) in dry THF (2 mL) at –50 ºC
under nitrogen. After 10 minutes, benzaldehyde (0.09 mL, 0.93 mmol)
was added. The mixture was allowed to warm slowly to room
temperature and MeOH (1 mL) was added. The solvent was evaporated
and a crude 1H NMR spectrum showed the product as a mixture of
stereoisomers (15:1). The mixture was absorbed onto silica then was
purified by flash column chromatography on silica gel, eluting with petrol–
EtOAc (75:25), to give the carbamate 7f (82 mg, 75%) (with the phenyl
groups trans as verified by X-ray crystallography, see page S-22) as
25.6, 125.4, 80.4, 79.8, 61.0, 59.4, 32.1, 31.2, 29.7, 29.5, 28.3, 28.2,
+
3.7, 23.0; HRMS (ES) Found: MH , 432.1909. C27
2
H30NO S requires
+
+
MH , 432.1906; LRMS m/z (ES) 432 (100%, MH ), 331 (45).
1
1-Phenyl-1-azatricyclo[9.4.0.02,7]pentadeca-2(7),3,5-triene
9:
Trifluoroacetic acid (0.23 mL, 3.0 mmol) was added to the carbamate 7d
100 mg, 0.31 mmol) in CH Cl (1 mL) at room temperature. After 1 h, the
solvent was evaporated then CH Cl (2 mL) and aqueous NaOH (5 mL, 2
M) were added. After 15 min, the organic layer was separated,
dried (MgSO ), and the solvent was evaporated. Purification by flash
silica chromatography, eluting with petrol–EtOAc (95:5), gave the amine
(
2
2
2
2
f
needles; m.p. 93–94 °C; R 0.43 [petrol–EtOAc (70:30)]; FT-IR νmax
film)/cm-1 3065, 2925, 2850, 1750; H NMR (400 MHz, CDCl
1H, d, J = 8 Hz, CH), 7.43–7.26 (9H, m, 9 × CH), 7.16–7.05 (4H, m, 4 ×
1
4
(
(
3
) δ = 7.50
9
(53 mg, 88%) as an oil; R
f
0.46 [petrol–EtOAc (60:40)]; FT-IR νmax
CH), 5.62 (1H, s, CH), 2.89–2.68 (2H, m, 2 × CH), 1.96–1.83 (3H, m, 3 ×
(film)/cm- 2990, 2875, 2750, 1150; H NMR (400 MHz, CDCl
1
1
CH), 1.56–1.45 (1H, m, CH); 13C NMR (101 MHz, CDCl
3
) δ = 7.60–
3
) δ = 156.3,
6
2
.82 (9H, m, 9 × CH), 3.55–3.25 (2H, m, 2 × CH), 3.13–2.85 (1H, m, CH),
.79–2.46 (1H, m, CH), 2.34–2.08 (1H, m, CH), 1.91–1.83 (1H, m, CH),
1
1
3
3
40.0, 138.0, 135.2, 133.1, 131.0, 130.3, 128.8, 128.6, 128.5, 128.3,
28.2, 128.0, 127.8, 127.2, 126.8, 126.1, 125.9, 125.7, 88.8, 70.0, 35.4,
+
requires MH+,
1.76–1.68 (1H, m, CH), 1.64–1.47 (5H, m, 5 × CH), 1.35–1.22 (2H, m, 2
× CH); 13C NMR (100 MHz, CDCl
) δ = 141.9, 137.3, 134.9, 133.8, 128.5,
28.2, 127.0, 125.7, 121.0, 120.3, 60.5, 47.9, 40.7, 30.6, 29.7, 26.2, 21.3,
3.6, 20.6; HRMS (ES) Found: MH , 356.1645. C24
H
22NO
2
56.1645; LRMS m/z (ES) 356 (100%, MH+).
3
1
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201800868
FULL PAPER
1
2
9.8; HRMS (ES) Found: MH+, 278.1906.
C
20
H
24
N
requires MH+,
m.p. 98–100 °C; R
f
0.26 [petrol–EtOAc (80:20)]; FT-IR νmax (film)/cm-1
78.1903; LRMS m/z (ES) 278 (100%, MH+).
2930, 1690, 1600; 1H NMR (400 MHz, CDCl
, rotamers) δ = 7.38–7.20
5.5H, m, CH), 7.07 (0.5H, d, J = 8.5 Hz, CH), 6.86 (0.5H, dd, J = 8.5, 3.0,
CH), 6.80–6.72 (1.5H, m, CH), 5.16 (0.5H, dd, J = 12.0, 3.0 Hz, CH), 4.91
0.5H, d, J = 12.0 Hz, CH), 3.84 (3H, s, CH ), 3.03–2.88 (1H, m, CH),
.64–2.54 (1H, m, CH), 2.01–1.89 (1H, m, CH), 1.83–1.65 (2H, m, 2 ×
CH), 1.56–1.47 (1H, m, CH), 1.33 (4H, s, t-Bu), 1.31 (5H, s, t-Bu); 13C
NMR (100 MHz, CDCl , rotamers) δ = 158.5, 158.3, 155.1, 155.0, 138.8,
38.5, 132.2, 132.0, 131.6, 131.4, 130.8, 130.6, 128.3, 128.1, 126.65,
3
(
Methyl 2-(2,3,4,5-Tetrahydro-1H-benzo[b]azepin-2-yl)benzoate 10:
Trifluoroacetic acid (0.20 mL, 2.6 mmol) was added to the carbamate 8a
(
2
3
(
100 mg, 0.26 mmol) in CH
solvent was evaporated then CH
M) were added. After 15 min, the organic layer was separated,
dried (MgSO ), and the solvent was evaporated. Purification by flash
silica chromatography, eluting with petrol–EtOAc (95:5), gave the amine
0 (63 mg, 86%) as an oil; R 0.15 [petrol–EtOAc (70:30)]; FT-IR νmax
film)/cm-1 3350, 2960, 2920, 1700; H NMR (400 MHz, CDCl
2
Cl
2
(1 mL) at room temperature. After 1 h, the
2
Cl (2 mL) and aqueous NaOH (5 mL, 2
2
3
1
1
5
4
26.6, 126.5, 126.1, 114.0, 113.5, 111.8, 111.5, 79.6, 79.4, 60.8, 59.2,
5.4, 55.3, 32.0, 31.1, 30.1, 29.9, 28.3, 28.2, 23.6, 23.0; HRMS (ES)
1
(
f
+
+
1
MNa , 376.1885. C22
H27NO
3
Na requires MNa , 376.1883; LRMS m/z (ES)
3
) δ = 8.03–
.78 (2H, m, 2 × CH), 7.66–7.34 (3H, m, 3 × CH), 7.14–7.04 (1H, m, CH),
.99–6.69 (2H, m, 2 × CH), 4.50–4.40 (1H, m, CH), 3.86 (3H, s, CH ),
.95–2.83 (2H, m, 2 × CH), 2.22–2.02 (2H, m, 2 × CH), 1.97–1.83 (1H, m,
) δ = 168.2,
49.1, 146.3, 138.6, 133.9, 132.4, 130.6, 129.8, 128.3, 127.1, 126.8,
+
376 (5%, MNa ), 298 (100).
7
6
2
3
tert-Butyl 7-Methoxy-2-phenyl-2-(tributylstannyl)-4,5-dihydro-3H-1-
benzazepine-1-carboxylate 14: nBuLi (0.15 mL, 0.33 mmol, 2.4 M in
hexane) was added to the carbamate 13 (100 mg, 0.28 mmol) in dry THF
(2 mL) at –50 ºC under nitrogen. After 10 minutes, tributyltin chloride
(0.22 mL, 0.84 mmol) was added. The mixture was allowed to warm to
room temperature over 16 h and MeOH (1 mL) was added. The solvent
was evaporated and the mixture was adsorbed onto silica. Purification by
flash column chromatography on silica gel, eluting with petrol–EtOAc
CH), 1.59–1.51 (1H, m, CH); 13C NMR (100 MHz, CDCl
3
1
1
2
+
21.3, 120.3, 59.3, 52.3, 39.8, 35.8, 26.6; HRMS (ES) Found: MH ,
82.1490. C18
+
H20NO
2
requires MH , 282.1489; LRMS m/z (ES) 282
(
100%, MH+).
N,6-Dimethoxy-1,2,3,4-tetrahydronaphthalen-1-amine
12:
O-
(
R
1
99:1), gave the carbamate 14 (118 mg, 65%) as needles; m.p. 86–88 ºC;
Methylhydroxylamine hydrochloride (2.83 g, 33.2 mmol) was added
dropwise to 6-methoxy-1-tetralone 11 (4.87 g, 27.7 mmol) and pyridine
0.53 [petrol–EtOAc (90:10)]; FT-IR νmax (film)/cm-1 2955, 1670, 1495;
) δ = 7.21 (2H, t, J = 8.0 Hz, 2 × CH), 7.12 (2H,
f
H NMR (400 MHz, CDCl
3
(
2.67 mL, 33.2 mmol) in methanol (60 mL) at room temperature. After 20
h, the solvent was evaporated and the mixture was poured into water
300 mL). Aqueous HCl (100 mL, 1 M) was added and the mixture was
extracted with CH Cl (3 × 150 mL). The organic layers were washed
with water (300 mL), dried (Na SO ), and the solvent was evaporated to
give the oxime (N,6-dimethoxy-3,4-dihydro-2H-naphthalen-1-imine) (5.19
br d, J = 8.0 Hz, CH), 6.98 (1H, t, J = 8.0 Hz, CH), 6.89 (1H, d, J = 9.0 Hz,
CH), 6.62 (1H, d, J = 3.0 Hz, CH), 6.55 (1H, dd, J = 9.0, 3.0 Hz, CH),
3
1
1
(
.74 (3H, s, OCH
.90–1.80 (2H, m, 2 × CH), 1.40–1.30 (16H, m, t-Bu, CH, 3 × CH
.21 (6H, m, 3 × CH ), 0.86 (9H, t, J = 7.0 Hz, 3 × CH ), 0.82–0.63 (6H,
); 13C NMR (100 MHz, CDCl
) δ = 158.0, 157.2, 139.6, 132.5,
3
), 2.95–2.82 (1H, m, CH), 2.57–2.44 (2H, m, 2 × CH),
2
2
2
), 1.28–
2
4
2
3
0.41 [petrol–EtOAc (80:20)]; FT-IR νmax (film)/cm-1
) δ = 7.95 (1H, d, J = 9.0 Hz,
m, 3 × CH
2
3
g, 91%) as an oil; R
f
1
130.9, 130.2, 128.8, 127.8, 123.7, 113.5, 110.8, 79.7, 68.2, 55.2, 30.4,
2
6
664.3000. C34
6
2940, 1615, 1590; H NMR (400 MHz, CDCl
3
+
9.1, 28.3, 27.7, 23.8, 23.0, 13.7, 13.5; HRMS (ES) Found: MNa ,
CH), 6.78 (1H, dd, J = 9.0, 3.0 Hz, CH), 6.66 (1H, d, J = 3.0 Hz, CH),
1
20
+
+
66.2972. C34
H
53NO
53NO
3
SnNa requires MNa , 666.2945; Found: MNa ,
3
1
1
.99 (3H, s, OCH
3
), 3.82 (3H, s, OCH
3
), 2.78–2.70 (4H, m, 4 × CH),
) δ = 160.2, 153.9,
41.3, 125.8, 123.5, 112.9, 112.7, 61.8, 55.2, 30.1, 24.2, 21.5; HRMS
118
+
.90–1.81 (2H, m, 2 × CH); 3C NMR (100 MHz, CDCl
1
H
3
SnNa requires MNa , 664.2940; LRMS m/z (ES)
3
66 (100%), 664 (80).
+
+
(ES) Found: MH , 206.1176. C12
2
H15NO , requires MH , 206.1176; LRMS
+
m/z (ES) 206 (100%, MH ). Sodium cyanoborohydride (3.08 g, 60 mmol)
was added dropwise to this oxime (10.0 g, 48 mmol) in methanol (100
mL) at 15 ºC. Methyl orange was added as an indicator and aqueous HCl
12-Methoxy-5,5-dimethyl-6-phenyl-4-oxa-2-
azatricyclo[8.4.0.02,6]tetradeca-1(10),11,13-trien-3-one 15: nBuLi (0.15
mL, 0.33 mmol, 2.4 M in hexane) was added to the carbamate 13 (100
mg, 0.28 mmol) in dry THF (2 mL) at –50 ºC under nitrogen. After 10
minutes, acetone (0.06 mL, 0.84 mmol) was added. The mixture was
allowed to warm to room temperature over 16 h and MeOH (1 mL) was
added. The solvent was evaporated and the mixture was adsorbed onto
silica. Purification by flash column chromatography on silica gel, eluting
with petrol–EtOAc (70:30), gave the carbamate 15 (74 mg, 78%) as
(
2 M) was added until the solution turned red. The mixture was stirred at
room temperature for 24 h then aqueous NaOH (50 mL, 2 M) was added
and the mixture was extracted with CH Cl (4 × 40 mL). The organic
layers were combined and washed with water (2 × 40 mL) and brine (20
mL), then dried (MgSO ). The solvent was evaporated to give
hydroxylamine 12 (6.22 g, 63%) as an oil; R 0.44 [petrol–EtOAc (90:10)];
FT-IR νmax (film)/cm-1 2940, 3400, 1610; 1H NMR (400 MHz, CDCl
) δ =
.26 (1H, d, J = 8.5 Hz, CH), 6.75 (1H, dd, J = 8.5, 3.0 Hz, CH), 6.65 (1H,
2
2
4
f
3
needles; m.p. 139–142 ºC; R
f
0.26 [petrol–EtOAc (60:40)]; FT-IR νmax
(film)/cm-1 2935, 1750, 1610; H NMR (400 MHz, CDCl
) δ = 7.48 (1H, d,
J = 9.0 Hz, CH), 7.44–7.13 (5H, m, 5 × CH), 6.86 (1H, dd, J = 9.0, 3.0 Hz,
CH), 6.59 (1H, d, J = 3.0 Hz, CH), 3.77 (3H, s, OCH ), 2.86–2.74 (2H, m,
2 × CH), 2.67 (1H, dd, J = 13.0, 6.0 Hz, CH), 2.27–2.16 (1H, m, CH),
1.98–1.89 (1H, m, CH), 1.54 (3H, s, CH ), 1.35–1.30 (1H, m, CH), 1.01
(3H, s, CH ) δ = 158.4, 156.9, 141.1, 136.4,
); 13C NMR (100 MHz, CDCl
1
7
3
3
d, J = 3.0 Hz, CH), 4.10 (1H, t, J = 4.5 Hz, CH), 3.79 (3H, s, OCH ), 3.60
(
1
3H, s, OCH
3
), 2.85–2.68 (2H, m, 2 × CH), 2.20–2.12 (1H, m, CH), 2.08–
.96 (1H, m, CH), 1.84–1.71 (2H, m, 2 × CH); 13C NMR (100 MHz, CDCl
)
3
3
δ = 158.7, 139.9, 130.7, 127.0, 113.6, 112.2, 62.3, 57.3, 55.2, 29.8, 26.4,
3
+
13O requires M+–
1
8.1; HRMS (ES) Found: M –NHOCH
3
, 161.0962. C11
H
3
3
NHOCH
3
, 161.0961; LRMS m/z (ES) 161 (100%).
132.2, 129.2, 128.2, 127.9, 127.4, 115.6, 112.2, 84.9, 71.9, 55.3, 36.4,
+
3
6.2, 26.1, 21.3, 21.1; HRMS (ES) Found: MH , 338.1757. C21
H
24NO
3
+
+
requires MH , 338.1751; LRMS m/z (ES) 360 (10%, MNa ), 338 (100,
MH+).
tert-Butyl 2,3,4,5-Tetrahydro-7-methoxy-2-phenylbenzo[b]azepine-1-
carboxylate 13: Phenyllithium (2.50 mL, 4.80 mmol, 1.9 M in Et O) was
added dropwise to the hydroxylamine 12 (322 mg, 1.60 mmol) in dry
Et O (10 mL) at 0 ºC. After 2 h, a solution of Boc O (1.00 g, 4.80 mmol)
in Et O (10 mL) was added dropwise and the mixture was warmed to
room temperature. After 16 h, Et O (10 mL) was added. The mixture was
washed with water (3 × 15 mL), dried (MgSO ), and the solvent was
2
2
2
tert-Butyl
2-(2-(Ethoxycarbonyl)phenyl)-7-methoxy-2,3,4,5-
2
tetrahydro-1-benzazepine-1-carboxylate 16: nBuLi (0.15 mL, 0.33
mmol, 2.4 M in hexane) was added to the carbamate 13 (100 mg, 0.28
mmol) in dry THF (2 mL) at –50 ºC under nitrogen. After 10 minutes,
ethyl chloroformate (0.08 mL, 0.84 mmol) was added. The mixture was
allowed to warm to room temperature over 16 h and MeOH (1 mL) was
2
4
evaporated. Purification by flash silica chromatography, eluting with
petrol–EtOAc (90:10), gave the carbamate 13 (420 mg, 77%) as needles,
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201800868
FULL PAPER
added. The solvent was evaporated and the mixture was adsorbed onto
silica. Purification by flash column chromatography on silica gel, eluting
with petrol–EtOAc (70:30), gave the carbamate 16 (72 mg, 60%) as an
2017, 53, 12229; f) A. Rahman, E. Xie, X. Lin, Org. Biomol. Chem.
2018, 16, 1367.
[5]
[6]
[7]
N. Carter, X. Li, L. Reavey, A. J. H. M. Meijer, I. Coldham, Chem. Sci.
2018, 9, 1352.
oil; R
f
0.52 [petrol–EtOAc (70:30)]; FT-IR νmax (film)/cm-1 2980, 1695,
1
1
500; H NMR (400 MHz, CDCl
3
, rotamers) δ = 7.91 (1H, d, J = 8.0 Hz,
T. Aeyad, J. D. Williams, A. J. H. M. Meijer, I. Coldham, Synlett 2017,
28, 2765.
CH), 7.59–7.57 (1H, m, CH), 7.52–7.48 (1H, m, CH), 7.23–7.20 (1H, m,
CH), 6.99–6.57 (3H, m, CH), 5.94 (0.25H, d, J = 12.0 Hz, CH), 5.77
a) R. A. Talk, A. Duperray, X. Li, I. Coldham, Org. Biomol. Chem. 2016,
14, 4908; b) E. J. Cochrane, L. A. Hassall, I. Coldham, J. Org. Chem.
2015, 80, 5964; c) X. Li, I. Coldham, J. Am. Chem. Soc. 2014, 136,
5551; d) E. J. Cochrane, D. Leonori, L. A. Hassall, I. Coldham, Chem.
Comm. 2014, 50, 9910; e) X. Li, D. Leonori, N. S. Sheikh, I. Coldham,
Chem. Eur. J. 2013, 19, 7724; f) N. S. Sheikh, D. Leonori, G. Barker, J.
D. Firth, K. R. Campos, A. J. H. M. Meijer, P. O’Brien, I. Coldham, J.
Am. Chem. Soc. 2012, 134, 5300; g) I. Coldham, D. Leonori, J. Org.
Chem. 2010, 75, 4069; h) S. P. Robinson, N. S. Sheikh, C. A. Baxter, I.
Coldham, Tetrahedron Lett. 2010, 51, 3642; i) I. Coldham, S. Raimbault,
D. T. E. Whittaker, P. T. Chovatia, D. Leonori, J. J. Patel, N. S. Sheikh,
Chem. Eur. J. 2010, 16, 4082.
(
0.75H, d, J = 12.0 Hz, CH), 4.45–4.37 (2H, m, OCH
OCH ), 3.79 (0.75H, s, OCH ), 3.00–2.93 (1H, m, CH), 2.64–2.58 (1H, m,
CH), 2.56–2.43 (1H, m, CH), 2.39–2.20 (1H, m, CH), 1.97–1.86 (2H, m, 2
CH), 1.44 (3H, t, J = 7.0, Hz, CH ), 1.35 (2.5H, s, t-Bu), 1.18 (6.5H, s, t-
Bu); 13C NMR (100 MHz, CDCl
, rotamers) δ = 167.2, 166.6, 158.3,
57.9, 155.0, 154.7, 150.4, 149.6, 138.5, 138.2, 132.3 (CH), 132.2 (CH),
30.8, 130.7, 130.1 (CH), 130.0 (CH), 129.4, 129.3, 127.4, 127.3, 127.0,
26.5, 125.9, 125.6, 113.9, 113.5, 111.7, 111.0, 80.1, 79.5, 61.1, 60.8,
7.0, 56.4, 55.4, 55.3, 31.8, 31.5, 29.9, 29.7, 28.2, 27.9, 23.9, 23.8, 14.3,
2
), 3.86–3.82 (3H, m,
3
3
×
3
3
1
1
1
5
1
4
+
requires MH+,
4.1; HRMS (ES) Found: MH , 426.2282. C25
H
32NO
5
+
26.2275; LRMS m/z (ES) 426 (25%, MH ), 370 (100), 326 (60).
[
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We thank the Ministry of Higher Education & Scientific Research,
Libya and the University of Sheffield for support. We are grateful
to Dr C. Robertson (University of Sheffield) for single crystal X-
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Keywords: Alkylation • Carbanions • Lithiation • Nitrogen
heterocycles • Quaternary centers
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European Journal of Organic Chemistry
10.1002/ejoc.201800868
FULL PAPER
Entry for the Table of Contents
FULL PAPER
Organolithium reactions
n-BuLi
Ph
Ph
Ph
T. Aeyad, C. G. Jones, I. Coldham*
THF, –50 °C
then R–X
N
N
N
Ph
t
O
Page No. – Page No.
CO Bu
2
O
R–X = Br(CH ) Br
2
4
Preparation of substituted tetrahydro-
R–X = PhCHO
then TFA, CH Cl
2
2
1-benzazepines by lithiation–trapping
‡
React-IR and VT-NMR spectroscopy (G 63 kJ/mol at –50 °C for Boc rotation)
were used to optimise the lithiation of N-Boc-2-phenyltetrahydro-1-benzazepine.
The intermediate organolithium was reacted with electrophiles to provide a
selection of substituted products, with functionalisation either at C-2 or at the ortho
position of the phenyl ring.
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