Synthesis of tricyclic lactams from heterocyclic imines

Article abstract of DOI:10.1055/s-0032-1316829

Starting from different heterocyclic imines, a large number of annulated tricyclic lactams were prepared in a two-step synthesis. First, methoxyamides with a phenyl ring in or β-position were 7generated. Finally, these substrates were converted to valero- and caprolactams, respectively, via intramolecular Friedel-Crafts cyclization in the presence of a Lewis acid. Additionally, effects of substituent groups at the phenyl ring in the electrophilic aromatic substitution were investigated.

Full text of DOI:10.1055/s-0032-1316829

PAPER
▌355
paper
Synthesis of Tricyclic Lactams from Heterocyclic Imines
Synthesis of Tricyclic Lactams
Timo Stalling, Jürgen Martens*
Institut für Reine und Angewandte Chemie, Carl von Ossietzky Universität Oldenburg, P. O. Box 2503, 26111 Oldenburg, Germany
Fax +49(441)7983329; E-mail: juergen.martens@uni-oldenburg.de
Received: 13.10.2012; Accepted after revision: 28.11.2012
Abstract: Starting from different heterocyclic imines, a large num-
ber of annulated tricyclic lactams were prepared in a two-step syn-
thesis. First, methoxyamides with a phenyl ring in α- or β-position
were generated. Finally, these substrates were converted to valero-
and caprolactams, respectively, via intramolecular Friedel–Crafts
cyclization in the presence of a Lewis acid. Additionally, effects of
substituent groups at the phenyl ring in the electrophilic aromatic
substitution were investigated.
R
R
n
n
O
O
OMe
N
N
N
X
X
X
X = S, O
n = 1, 2
Key words: heterocycles, imines, amides, lactams, cyclization,
electrophilic aromatic substitution
Scheme 1 Retrosynthetic consideration of the target structure
Lactam systems are popular and widely used substruc-
tures due to their multifaceted possible uses.1 In view of
their prevalence in biologically active compounds,2–6 the
development of methods to prepare these molecules is still
in the focus of many investigations.7 Based on these facts
a range of synthetic routes were published.8 Apart from
that, articles dealing with a general access starting from
imines, especially from cyclic imines, are extremely sel-
dom, whereas syntheses of β-lactams are well studied.9
On the other hand, synthetic routes involving several
kinds of reactive N-acyliminium ions, which often play a
dominant role in the environment of imines, are well
known.10 However, some of these methods feature several
disadvantages such as harsh reaction conditions, costly
and sensitive reagents, or long reaction times.10
context, a large number of different substituents at the
five-membered imine were investigated and offer the pos-
sibility to examine their effects in consecutive reactions.
The new two-step reaction sequence for preparing differ-
ent classes of lactams is based on heterocyclic imines. The
known precursor compounds 1, 2,5-dihydrothiazoles and
2,5-dihydrooxazole, were synthesized by a modified
Asinger protocol in a multicomponent reaction.16,17
Choosing an α-chloroaldehyde, a second variable carbon-
yl compound, ammonia, and sodium hydrosulfide or wa-
ter in dichloromethane, the monocyclic imines 1 were
obtained in a one-pot reaction in good yields (up to 73%)
(Scheme 2).
NH3
O
Thus, cyclic imines are suitable starting materials for such
a targeted synthetic pathway generating different types of
new lactam structures due to their reactive C=N bond in
the ring. In the recent past, we often took advantage of this
property to form lactam structures.11 In combination with
the addition of acyl chlorides, which was previously es-
tablished in our group,12 an array of tricyclic lactams with
an annulated phenyl ring based on cyclic imines was
available in only two steps (Scheme 1). The lactamization
was completed by means of a Lewis acid as part of an in-
tramolecular Friedel–Crafts cyclization. Bearing the iso-
quinoline skeleton, the target structures could attract a
great deal of attention in the pharmacological field. Simi-
lar isoquinoline derivatives are known as receptor
agonist13 or anticonvulsant agent.14
R1
R2
N
CH2Cl2, 0 °C to r.t.
R3
R4
R1
R2
R3
R4
O
Cl
X
NaSH
or
H2O
1
Scheme 2 Synthesis of 2,5-dihydrothiazoles and 2,5-dihydrooxa-
zole 1 (R1–R4 = alkyl; X = S, O)16,17
In the first step of the described synthesis, the imines 1
were treated with acyl chlorides, which are characterized
by a phenyl ring in the α- or β-position (Scheme 3). The
substitution pattern at the phenyl ring was selected consid-
ering directing effects on the aromatic substitution in the
last step. Without isolation of the resulting hydrolysis-
sensitive chloroamides, addition of methanol in the pres-
ence of triethylamine led to the racemic methoxyamides 2
and 3.
Due to the high pharmacological activity of their corre-
sponding amines, 2,5-dihydrothiazoles and -oxazoles
were selected as applicable starting materials.15 In this
The described procedure affords the desired methoxyam-
ides 2 and 3 in good to excellent yields of up to 99% after
workup by column chromatography (Table 1). It should
be noted in particular that the amides 2i and 3b, which be-
long to the class of oxazolidines, resulted in higher yields
than the corresponding thiazolidine compounds 2c and 3a,
SYNTHESIS 2013, 45, 0355–0364
Advanced online publication: 21.12.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1316829; Art ID: SS-2012-T0804-OP
© Georg Thieme Verlag Stuttgart · New York

356
T. Stalling, J. Martens
PAPER
iminium ions were generated. These intermediates are
predestined to react with an aromatic compound.10 In this
manner, the methoxyamides were successfully converted
to the six-membered valerolactams 4 in an intramolecular
Friedel–Crafts cyclization. To extend the utility and to es-
tablish the diversity of this strategy, the procedure was
also applied exemplary to the synthesis of the seven-
membered caprolactams 6.
R5
R5
n
1.
O
Cl
n
O
OMe
2. MeOH, Et3N
N
N
R1
R2
R3
R4
R1
R2
R3
R4
CH2Cl2, 0 °C to r.t.
X
X
1
2, 3
R5
Scheme 3 Synthesis of the methoxyamides 2 and 3 starting from the
heterocyclic imines 1 (R1–R4 = alkyl; R5 = H, Me, OMe; n = 1, 2)
(yields are given in Table 1)
n
O
AlCl3
N
2, 3
R1
R2
R3
R4
CH2Cl2, 0 °C to r.t.
respectively. Concerning the substituent at the phenyl
ring, the best result was achieved with the unsubstituted
substrate (i.e., 2a, 99%). Apart from that, a significant de-
pendence of the yields on the substituents at the phenyl
ring, the five-membered imine ring, or on the chain length
of the acyl group cannot be noticed.
X
R5
R5
n
n
Table 1 Methoxyamides 2 and 3
O
O
N
N
R5
R1
R2
R3
R4
R1
R2
R3
R4
X
X
4, 6
R5
Scheme 4 Synthesis of the lactams 4 and 6 starting from the meth-
oxyamides 2 and 3 (R1–R4 = alkyl; R5 = H, Me, OMe; n = 1, 2)
(yields are given in Table 2)
O
O
OMe
OMe
N
N
R1
R2
R3
R4
R1
R2
R3
R4
X
X
Following this synthetic route, the racemic lactams 4 and
6 resulted predominantly in high yields (up to ~100%) af-
ter workup by column chromatography in several cases
(Table 2). It is worth mentioning that the lactams 4c, 4e,
4i, and 6a were obtained in pure form without any further
purification. Unlike in the synthesis of all other lactams,
we failed to obtain a good yield of the valerolactam 4d
(8%).
Analysis of all the crude products by 1H NMR spectrosco-
py showed a single regioisomer of valero- and caprolac-
tams 4 and 6. Due to steric hindrance, the substitution
occurs only in the para position of the mentioned groups.
These assumptions are based on the interpretation of the
NMR data of 4 and 6 and are verified by the X-ray crystal
structure determination of 4i (see below). As known,
methyl and methoxy groups increase the rate of reaction
due to their donating electron inductive and resonance ef-
fect, respectively. The conversion of the substrates 2c, 2e,
and 2h with a methoxy group at the phenyl ring provided
correspondingly higher yields (up to ~100%) in compari-
son with the compounds 2b, 2d, and 2g (up to 38%) con-
taining a methyl group at the phenyl ring. Based on this
knowledge, an activated aromatic compound (R5 = OMe)
was systematically chosen in the case of the methoxy-
amides 3 to achieve high yields. This goal was easily ac-
complished with the excellent yields of 94% (i.e., 6a) and
~100% (i.e., 6b).
2
3
Entry Imine Amide X R1
R2
R3
R4
R5
Yield
(%)a
1
1a
1a
1a
1b
1b
1c
1d
1d
1e
1a
1e
2a
2b
2c
2d
2e
2f
S
S
S
S
S
S
S
S
O
S
O
Me
Me
Me
Me Me Me
Me Me Me
Me Me Me
H
99
49
2
Me
3
OMe 61
Me 65
4
–(CH2)5–
–(CH2)5–
Me Me
Me Me
–(CH2)5–
–(CH2)5–
–(CH2)5–
5
OMe 38
OMe 72
6
Me
Me
7
2g
2h
2i
–(CH2)5–
–(CH2)5–
Me
67
8
OMe 24
OMe 67
OMe 53
OMe 88
9
Me
Me
Me
Me Me Me
Me Me Me
Me Me Me
10
11
3a
3b
a Isolated yields.
The next step of the synthetic strategy towards tricyclic
lactams was initiated by treating the methoxyamides 2 and
3 with the Lewis acid aluminum trichloride (Scheme 4).
By elimination of the methoxy group, reactive N-acyl-
Synthesis 2013, 45, 355–364
© Georg Thieme Verlag Stuttgart · New York

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Synthesis of Tricyclic Lactams
357
Table 2 Lactams 4, 6, and Hydroxyamides 5
R5
R5
R5
O
O
OH
O
N
N
N
R1
R2
R3
R4
R1
R2
R3
R4
R1
R2
R3
R4
X
X
X
4
5
6
Entry
Amide
Lactam
X
R1
R2
R3
R4
R5
Yield (%)a
1
2a
2b
2c
2d
2e
2f
4a
4b
4c
4d
4e
4f
S
S
S
S
S
S
S
S
O
S
O
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
25 (31)b
35 (43)b
75
2
Me
3
OMe
Me
4
–(CH2)5–
–(CH2)5–
8 (35)b
~100
69
5
OMe
OMe
Me
6
Me
Me
–(CH2)5–
–(CH2)5–
–(CH2)5–
7
2g
2h
2i
4g
4h
4i
–(CH2)5–
–(CH2)5–
38 (27)b
85
8
OMe
OMe
OMe
OMe
9
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
97
10
11
3a
3b
6a
6b
94
~100
a Isolated yields.
b Yield of the respective hydroxyamide 5, which results as a by-product.
Cyclization of the methoxyamides 2a, 2b, 2d, and 2g led
to the hydroxyamides 5 as the by-product. In regard to the
discussion above, this fact documents an insufficient acti-
vation of the phenyl rings for further substitution. Instead,
the reactive N-acyliminium ions are quenched with water
in the course of the aqueous purification forming the hy-
droxyamides 5. This fact gives an adequate explanation
for the unsatisfactory yields in the reaction of the lactams
4a, 4b, 4d, and 4g.
Supplemental to the methoxy group, the methoxyamides
2 and 3 contain additional Lewis basic functional groups,
such as an amide group and a sulfide or an ether group.
This fact justifies the use of 2.5 equivalents of aluminum
trichloride in order to separate the methoxy group com-
pletely.
Figure 1 X-ray crystal structure of the racemic valerolactam 4i (only
one enantiomer is shown).18 The atom-numbering in the X-ray struc-
ture does not follow the IUPAC nomenclature.
As mentioned above, only a single regioisomer was found
in the 1H NMR spectra of the crude lactams 4 and 6. In the
case of the racemic valerolactam 4i, single crystals could
be obtained and the proposed structural features were es-
tablished by X-ray analysis (Figure 1).
constitution of all other prepared lactams 4 and 6 was as-
signed by analogy comparing the NMR data with 4i.
The X-ray crystal structure determination of 4i verifies the
postulated constitution and moreover proves the expected
position of the relatively voluminous substituent at the
phenyl ring due to steric hindrance. Consequently, the
In conclusion, we have presented a new two-step se-
quence for the synthesis of different types of lactams start-
ing from the heterocyclic imines 1. Treating these
precursors with an acyl chloride followed by addition of
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 355–364

358
T. Stalling, J. Martens
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1H NMR (500.1 MHz, CDCl3): δ = 1.04, 1.32, 1.83, 1.91 [4 s, 12 H,
2 × C(CH3)2], 3.50 (s, 3 H, OCH3), 3.82 (d, 2J = 15.8 Hz, 1 H, CH2),
3.85 (d, 2J = 15.6 Hz, 1 H, CH2), 4.87 (s, 1 H, NCH), 7.24–7.26 (m,
3 H, 2 × o-CHAr, p-CHAr), 7.31–7.34 (m, 2 H, m-CHAr).
13C NMR (125.8 MHz, CDCl3): δ = 23.3, 30.4, 30.9, 31.7 [2 ×
C(CH3)2], 44.6 (CH2), 52.9 [C(CH3)2CH], 56.1 (OCH3), 72.6
[C(CH3)2N], 99.3 (NCH), 127.3 (p-CHAr), 128.9, 128.9 (2 × o-
CHAr, 2 × m-CHAr), 134.8 (CAr), 170.4 (C=O).
methanol, the methoxyamides 2 and 3 were obtained in up
to quantitative yields. Finally, the desired lactamization
was initiated by means of the Lewis acid aluminum tri-
chloride. Via an intramolecular Friedel–Crafts cycliza-
tion, the annulated tricyclic valerolactams 4 and
caprolactams 6 were obtained in good to excellent yields
depending on the influence of the substituent at the phenyl
ring. The constitution of the lactams 4 and 6 was clarified
by a single-crystal X-ray structure analysis of a selected
valerolactam 4.
MS (CI, isobutane): m/z (%) = 294.3 (84, [MH]+).
HRMS (CI, isobutane): m/z calcd for C16H24NO2S+: 294.1528;
found: 294.1526.
(RS)-1-(4-Methoxy-2,2,5,5-tetramethyl-1,3-thiazolidin-3-yl)-2-
(3-methylphenyl)ethan-1-one (2b)
Synthetic procedures under argon atmosphere were performed on a
vacuum line using standard Schlenk techniques. Preparative col-
umn chromatography was carried out using Grace SiO2 (0.035–
0.070 mm, type KG 60). TLC was performed on Merck SiO2 F254
plates on aluminum sheets. Melting points were obtained on a melt-
ing point apparatus of Laboratory Devices and are uncorrected. 1H
and 13C NMR spectra were recorded on a Bruker AMX R 500 (mea-
suring frequency: 1H NMR = 500.1 MHz, 13C NMR = 125.8 MHz)
Following GP A, dihydrothiazole 1a (286 mg, 2.00 mmol), 2-(3-
methylphenyl)acetyl chloride (371 mg, 2.20 mmol), anhyd MeOH
(237 mg, 300 μL, 7.40 mmol), and anhyd Et3N (354 mg, 485 μL,
3.50 mmol) were used. The crude product was purified by column
chromatography (silica gel; n-hexane–EtOAc, 4:1); yield: 300 mg
(49%); colorless, extremely viscous oil; Rf = 0.43 (n-hexane–
EtOAc, 4:1).
or
a
Bruker Avance III 500 (measuring frequency:
1H NMR = 499.9 MHz, 13C NMR = 125.7 MHz) spectrometer in
CDCl3 solution. As an internal standard, the residual signal was
used [7.26 ppm (1H NMR), 77.16 ppm (13C NMR)].19 Assignments
of the signals were supported by measurements applying DEPT and
IR (ATR): 2981, 2932, 2867, 2828, 1658, 1610, 1592, 1490, 1467,
1449, 1388, 1368, 1270, 1213, 1197, 1167, 1142, 1081, 927, 765,
726, 695 cm–1.
1H NMR (500.1 MHz, CDCl3): δ = 1.06, 1.33, 1.83, 1.92 [4 s, 12 H,
1
COSY techniques. The abbreviation n.r. in the H NMR spectral
2 × C(CH3)2], 2.33 (s, 3 H, CArCH3), 3.51 (s, 3 H, OCH3), 3.78 (d,
2
2J = 15.9 Hz, 1 H, CH2), 3.81 (d, J = 15.7 Hz, 1 H, CH2), 4.88 (s,
data of 3b (2 ×) and 4f (1 ×) denotes not resolved. Mass spectra were
obtained on a Finnigan-MAT 95 mass spectrometer with isobutane
as the reagent gas. The IR spectra were recorded with a Bruker
Tensor 27 spectrometer equipped with a ‘Golden Gate’ diamond-
ATR (attenuated total reflection) unit. 2-Phenylacetyl chloride,20 2-
(3-methylphenyl)acetyl chloride,21 2-(3-methoxyphenyl)acetyl
chloride,22 2,2,5,5-tetramethyl-2,5-dihydrothiazole (1a),23 2,2-di-
1 H, NCH), 7.03–7.07 (m, 3 H, p-CHArCH2, o-CHArCH3, p-
CHArCH3), 7.20–7.23 (m, 1 H, m-CHAr).
13C NMR (125.8 MHz, CDCl3): δ = 21.5 (CArCH3), 23.4, 30.4,
30.9, 31.7, [2 × C(CH3)2], 44.6 (CH2), 52.9 [C(CH3)2CH], 56.1
(OCH3), 72.6 [C(CH3)2N], 99.3 (NCH), 126.0, 128.0 (2 × CHAr),
128.8 (m-CHAr), 129.6 (CHAr), 134.7 (CArCH2), 138.6 (CArCH3),
170.6 (C=O).
methyl-1-thia-4-azaspiro[4.5]dec-3-ene (1b),24
thia-3-azaspiro[4.5]dec-3-ene
(1c),25
2,2-dimethyl-1-
7-thia-14-azadispi-
MS (CI, isobutane): m/z (%) = 308.3 (100, [MH]+), 276.2 (46, [MH
ro[5.1.58.26]pentadec-14-ene (1d),26 and 2,2,5,5-tetramethyl-2,5-
dihydro-oxazole (1e)17 were prepared according to published proce-
dures. CH2Cl2 was refluxed with CaH2 and freshly distilled prior to
use. MeOH was refluxed with Mg and freshly distilled prior to use.
Et3N was dried over molecular sieves and freshly distilled prior to
use.
– CH4O]+).
HRMS (CI, isobutane): m/z calcd for C17H26NO2S+: 308.1684;
found: 308.1684.
(RS)-1-(4-Methoxy-2,2,5,5-tetramethyl-1,3-thiazolidin-3-yl)-2-
(3-methoxyphenyl)ethan-1-one (2c)
Methoxyamides 2 and 3; General Procedure A (GP A)
Under argon atmosphere, the respective imine 1 (1 equiv), dissolved
in anhyd CH2Cl2 (2 mL per mmol imine), was cooled down to 0–
5 °C. A solution of the respective acyl chloride (1.1 equiv) in anhyd
CH2Cl2 (3 mL per mmol imine) was added dropwise. After stirring
for 5 h at r.t., a solution of anhyd MeOH (3.7 equiv) and anhyd Et3N
(1.75 equiv) in anhyd CH2Cl2 (2 mL per mmol imine) was added
dropwise at 0–5 °C. After stirring overnight at r.t., the solution was
poured into ice-water (7 mL per mmol imine). The phases were sep-
arated and the aqueous phase was extracted with CH2Cl2 (3 × 4 mL
per mmol imine). The combined organic phases were washed with
sat. aq NaHCO3 (1 × 4 mL per mmol imine), H2O (1 × 4 mL per
mmol imine), and dried (MgSO4). The solvent was removed on a ro-
tary evaporator. The crude product was purified as described below
for individual cases.
Following GP A, dihydrothiazole 1a (280 mg, 1.95 mmol), 2-(3-
methoxyphenyl)acetyl chloride (397 mg, 2.15 mmol), anhyd
MeOH (231 mg, 292 μL, 7.22 mmol), and anhyd Et3N (345 mg,
473 μL, 3.41 mmol) were used. The crude product was purified by
column chromatography (silica gel; n-hexane–MTBE, 7:3); yield:
385 mg (61%); yellow solid; mp 37–38 °C; Rf = 0.32 (n-hexane–
MTBE, 7:3).
IR (ATR): 3005, 2970, 2932, 2893, 2837, 2820, 1642, 1609, 1584,
1453, 1371, 1252, 1152, 1139, 1085, 925, 765, 720 cm–1.
1H NMR (500.1 MHz, CDCl3): δ = 1.07, 1.33, 1.84, 1.93 [4 s, 12 H,
2 × C(CH3)2], 3.51 (s, 3 H, NCHOCH3), 3.79 (s, 3 H, CArOCH3),
3.80, 3.84 (2 d, 2J = 15.2 Hz, 2 H, CH2), 4.88 (s, 1 H, NCH), 6.80–
6.85 (m, 3 H, p-CHArCH2, o-CHArOCH3, p-CHArOCH3), 7.24–7.28
(m, 1 H, m-CHAr).
13C NMR (125.8 MHz, CDCl3): δ = 23.3, 30.4, 30.9, 31.6 [2 ×
C(CH3)2], 44.7 (CH2), 52.9 [C(CH3)2CH], 55.3 (CArOCH3), 56.1
(NCHOCH3), 72.6 [C(CH3)2N], 99.3 (NCH), 112.7 (p-CHArCH2),
114.4 (o-CHArOCH3), 121.2 (p-CHArOCH3), 129.9 (m-CHAr), 136.3
(CArCH2), 160.0 (CArOCH3), 170.3 (C=O).
(RS)-1-(4-Methoxy-2,2,5,5-tetramethyl-1,3-thiazolidin-3-yl)-2-
phenylethan-1-one (2a)
Following GP A, dihydrothiazole 1a (320 mg, 2.24 mmol), 2-phen-
ylacetyl chloride (380 mg, 2.46 mmol), anhyd MeOH (261 mg,
330 μL, 8.14 mmol), and anhyd Et3N (411 mg, 563 μL, 4.07 mmol)
were used. The crude product was purified by column chromatog-
raphy (silica gel; n-hexane–MTBE, 4:1); yield: 647 mg (99%); col-
orless, extremely viscous oil; Rf = 0.24 (n-hexane–MTBE, 4:1).
MS (CI, isobutane): m/z (%) = 324.1 (91, [MH]+), 292.1 (100, [MH
– CH4O]+).
HRMS (CI, isobutane): m/z calcd for C17H26NO3S+: 324.1633;
found: 324.1640.
IR (ATR): 2979, 2931, 2827, 1654, 1604, 1584, 1496, 1454, 1387,
1367, 1264, 1210, 1195, 1165, 1140, 1080, 923, 718, 696 cm–1.
Synthesis 2013, 45, 355–364
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PAPER
Synthesis of Tricyclic Lactams
359
(RS)-1-(3-Methoxy-2,2-dimethyl-1-thia-4-azaspiro[4.5]decan-
4-yl)-2-(3-methylphenyl)ethan-1-one (2d)
485 μL, 3.50 mmol) were used. The crude product was purified by
column chromatography (silica gel; n-hexane–EtOAc, 4:1); yield:
522 mg (72%); colorless solid; mp 45 °C; Rf = 0.33 (n-hexane–
EtOAc, 4:1).
Following GP A, dihydrothiazole 1b (367 mg, 2.00 mmol), 2-(3-
methylphenyl)acetyl chloride (371 mg, 2.20 mmol), anhyd MeOH
(237 mg, 300 μL, 7.40 mmol), and anhyd Et3N (354 mg, 485 μL,
3.50 mmol) were used. The crude product was purified by column
chromatography (silica gel; n-hexane–EtOAc, 4:1); yield: 448 mg
(65%); colorless solid; mp 100 °C; Rf = 0.49 (n-hexane–EtOAc,
4:1).
IR (ATR): 3001, 2971, 2929, 2852, 2834, 1638, 1610, 1583, 1488,
1456, 1435, 1378, 1353, 1282, 1183, 1166, 1148, 1076, 895, 773,
722 cm–1.
1H NMR (500.1 MHz, CDCl3): δ = 1.07–1.32 (m, 5 H, CH2,Cy),
1.41–1.44 (m, 1 H, CH2,Cy), 1.51–1.67 (m, 4 H, CH2,Cy), 1.84, 1.90
[2 s, 6 H, C(CH3)2], 3.50 (s, 3 H, NCHOCH3), 3.80 (d, 2J = 15.2 Hz,
IR (ATR): 3020, 3007, 2984, 2965, 2926, 2861, 2851, 2821, 1661,
1625, 1609, 1591, 1492, 1464, 1455, 1384, 1366, 1271, 1259, 1244,
1179, 1144, 1086, 920, 778, 758, 720, 695 cm–1.
2
1 H, CH2CAr), 3.80 (s, 3 H, CArOCH3), 3.85 (d, J = 15.2 Hz, 1 H,
CH2CAr), 4.96 (s, 1 H, NCH), 6.81–6.84 (m, 3 H, p-CHArCH2, o-
CHArOCH3, p-CHArOCH3), 7.24–7.28 (m, 1 H, m-CHAr).
1H NMR (500.1 MHz, CDCl3): δ = 1.04 [s, 3 H, C(CH3)2], 1.12–
1.22, 1.27–1.36 (2 m, 2 H, CH2,Cy), 1.32 [s, 3 H, C(CH3)2], 1.51–
1.59 (m, 3 H, CH2,Cy), 1.67–1.78 (m, 2 H, CH2,Cy), 1.87–1.89 (m,
1 H, CH2,Cy), 2.32 (s, 3 H, CArCH3), 2.75–2.81, 3.17–3.22 (2 m, 2 H,
CH2,Cy), 3.49 (s, 3 H, OCH3), 3.78 (d, 2J = 15.4 Hz, 1 H, CH2CAr),
3.81 (d, 2J = 15.2 Hz, 1 H, CH2CAr), 4.91 (s, 1 H, NCH), 7.02–7.06
(m, 3 H, p-CHArCH2, o-CHArCH2, p-CHArCH3), 7.19–7.22 (m, 1 H,
m-CHAr).
13C NMR (125.8 MHz, CDCl3): δ = 21.5 (CArCH3), 23.5 [C(CH3)2],
24.6, 25.1, 25.9 (3 × CH2,Cy), 30.4 [C(CH3)2], 36.7, 38.2 (2 ×
CH2,Cy), 45.2 (CH2CAr), 52.0 [C(CH3)2], 56.1 (OCH3), 80.2
[C(CH2,Cy)5], 99.1 (NCH), 126.0, 127.9 (2 × CHAr), 128.8 (m-CHAr),
129.7 (CHAr), 134.8 (CArCH2), 138.5 (CArCH3), 170.9 (C=O).
13C NMR (125.8 MHz, CDCl3): δ = 22.2, 24.4, 25.6 (3 × CH2,Cy),
31.0, 32.1 [C(CH3)2], 33.2, 37.4 (2 × CH2,Cy), 44.5 (CH2CAr), 55.3
(CArOCH3), 56.0 (NCHOCH3), 59.1 [C(CH2,Cy)5], 71.6 [C(CH3)2],
98.6 (NCH), 112.7 (p-CHArCH2), 114.4 (o-CHArOCH3), 121.2 (p-
CHArOCH3), 129.9 (m-CHAr), 136.3 (CAr CH2), 160.0 (CArOCH3),
170.5 (C=O).
MS (CI, isobutane): m/z (%) = 364.4 (99, [MH]+), 332.3 (100, [MH
– CH4O]+).
HRMS (CI, isobutane): m/z calcd for C20H30NO3S+: 364.1946;
found: 364.1955.
(RS)-1-(15-Methoxy-7-thia-14-azadispiro[5.1.58.26]pentadecan-
14-yl)-2-(3-methylphenyl)ethan-1-one (2g)
MS (CI, isobutane): m/z (%) = 348.3 (54, [MH]+), 316.3 (100, [MH
– CH4O]+).
Following GP A, dihydrothiazole 1d (447 mg, 2.00 mmol), 2-(3-
methylphenyl)acetyl chloride (371 mg, 2.20 mmol), anhyd MeOH
(237 mg, 300 μL, 7.40 mmol), and anhyd Et3N (354 mg, 485 μL,
3.50 mmol) were used. The crude product was purified by column
chromatography twice (silica gel; 1. n-hexane–EtOAc, 7:3; 2.
CH2Cl2–n-hexane, 4:1); yield: 516 mg (67%); colorless solid; mp
79–82 °C; Rf = 0.73 (n-hexane–EtOAc, 7:3).
HRMS (CI, isobutane): m/z calcd for C20H30NO2S+: 348.1997;
found: 348.1990.
(RS)-1-(3-Methoxy-2,2-dimethyl-1-thia-4-azaspiro[4.5]decan-
4-yl)-2-(3-methoxyphenyl)ethan-1-one (2e)
Following GP A, dihydrothiazole 1b (367 mg, 2.00 mmol), 2-(3-
methoxyphenyl)acetyl chloride (406 mg, 2.20 mmol), anhyd
MeOH (237 mg, 300 μL, 7.40 mmol), and anhyd Et3N (354 mg,
485 μL, 3.50 mmol) were used. The crude product was purified by
column chromatography (silica gel; n-hexane–MTBE, 9:1); yield:
278 mg (38%); colorless, extremely viscous oil; Rf = 0.08 (n-hex-
ane–MTBE, 9:1).
IR (ATR): 2929, 2856, 1657, 1610, 1591, 1491, 1451, 1372, 1273,
1254, 1179, 1081, 895, 764, 719, 694 cm–1.
1H NMR (500.1 MHz, CDCl3): δ = 1.04–1.77 (m, 16 H, CH2,Cy),
1.87–1.88 (m, 2 H, CH2,Cy), 2.32 (s, 3 H, CArCH3), 2.74–2.78, 3.16–
3.20 (2 m, 2 H, CH2,Cy), 3.47 (s, 3 H, OCH3), 3.79–3.80 (m, 2 H,
CH2CAr), 4.98 (s, 1 H, NCH), 7.01–7.06 (m, 3 H, p-CHArCH2, o-
CHArCH2, p-CHArCH3), 7.19–7.22 (m, 1 H, m-CHAr).
13C NMR (125.8 MHz, CDCl3): δ = 21.5 (CArCH3), 22.2, 24.3,
24.6, 25.0, 25.6, 25.8, 33.3, 37.1, 37.2, 38.2 (10 × CH2,Cy), 45.0
(CH2CAr), 56.0 (OCH3), 58.0 [C(CH2,Cy)5CH], 79.1 [C(CH2,Cy)5N],
98.4 (NCH), 126.0, 127.9 (2 × CHAr), 128.7 (m-CHAr), 129.7
(CHAr), 134.8 (CArCH2), 138.5 (CArCH3), 171.0 (C=O).
IR (ATR): 2930, 2857, 2834, 1654, 1600, 1585, 1491, 1453, 1439,
1386, 1367, 1299, 1254, 1165, 1140, 1083, 1049, 922, 767, 718,
691 cm–1.
1H NMR (500.1 MHz, CDCl3): δ = 1.03 [s, 3 H, C(CH3)2], 1.13–
1.21, 1.26–1.35 (2 m, 2 H, CH2,Cy), 1.31 [s, 3 H, C(CH3)2], 1.51–
1.59 (m, 3 H, CH2,Cy), 1.69–1.78 (m, 2 H, CH2,Cy), 1.86–1.88, 2.75–
2.81, 3.17–3.21 (3 m, 3 H, CH2,Cy), 3.49 (s, 3 H, NCHOCH3), 3.78
2
(d, J = 15.3 Hz, 1 H, CH2CAr), 3.78 (s, 3 H, CArOCH3), 3.82 (d,
MS (CI, isobutane): m/z (%) = 388.2 (33, [MH]+), 356.2 (100, [MH
2J = 15.3 Hz, 1 H, CH2CAr), 4.90 (s, 1 H, NCH), 6.77–6.82 (m, 3 H,
p-CHArCH2, o-CHArOCH3, p-CHArOCH3), 7.21–7.24 (m, 1 H, m-
CHAr).
– CH4O]+).
HRMS (CI, isobutane): m/z calcd for C23H34NO2S+: 388.2310;
found: 388.2301.
13C NMR (125.8 MHz, CDCl3): δ = 23.5 [C(CH3)2], 24.6, 25.1,
25.9 (3 × CH2,Cy), 30.3 [C(CH3)2], 36.7, 38.2 (2 × CH2,Cy), 45.3
(CH2CAr), 52.0 [C(CH3)2], 55.3 (CArOCH3), 56.1 (NCHOCH3), 80.2
[C(CH2,Cy)5], 99.1 (NCH), 112.7 (p-CHArCH2), 114.5 (o-
CHArOCH3), 121.3 (p-CHArOCH3), 129.9 (m-CHAr), 136.4
(CArCH2), 160.0 (CArOCH3), 170.6 (C=O).
(RS)-1-(15-Methoxy-7-thia-14-azadispiro[5.1.58.26]pentadecan-
14-yl)-2-(3-methoxyphenyl)ethan-1-one (2h)
Following GP A, dihydrothiazole 1d (447 mg, 2.00 mmol), 2-(3-
methoxyphenyl)acetyl chloride (406 mg, 2.20 mmol), anhyd
MeOH (237 mg, 300 μL, 7.40 mmol), and anhyd Et3N (354 mg,
485 μL, 3.50 mmol) were used. The crude product was purified by
column chromatography (silica gel; n-hexane–MTBE, 9:1); yield:
193 mg (24%); colorless, extremely viscous oil; Rf = 0.08 (n-hex-
ane–MTBE, 9:1).
MS (CI, isobutane): m/z (%) = 364.2 (88, [MH]+), 332.2 (100, [MH
– CH4O]+).
HRMS (CI, isobutane): m/z calcd for C20H30NO3S+: 364.1946;
found: 364.1944.
IR (ATR): 2928, 2855, 1653, 1600, 1585, 1491, 1450, 1371, 1300,
1253, 1176, 1149, 1079, 1050, 893, 767, 729, 691 cm–1.
(RS)-1-(4-Methoxy-2,2-dimethyl-1-thia-3-azaspiro[4.5]decan-
3-yl)-2-(3-methoxyphenyl)ethan-1-one (2f)
Following GP A, dihydrothiazole 1c (367 mg, 2.00 mmol), 2-(3-
methoxyphenyl)acetyl chloride (406 mg, 2.20 mmol), anhyd
MeOH (237 mg, 300 μL, 7.40 mmol), and anhyd Et3N (354 mg,
1H NMR (500.1 MHz, CDCl3): δ = 1.01–1.77 (m, 16 H, CH2,Cy),
1.86–1.88 (m, 2 H, CH2,Cy), 2.74–2.78, 3.16–3.20 (2 m, 2 H,
CH2,Cy), 3.47 (s, 3 H, NCHOCH3), 3.78 (s, 3 H, CArOCH3), 3.79 (d,
2
2J = 15.2 Hz, 1 H, CH2CAr), 3.83 (d, J = 15.3 Hz, 1 H, CH2CAr),
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 355–364

360
T. Stalling, J. Martens
PAPER
4.97 (s, 1 H, NCH), 6.78–6.82 (m, 3 H, p-CHArCH2, o-CHArOCH3,
p-CHArOCH3), 7.21–7.24 (m, 1 H, m-CHAr).
HRMS (CI, isobutane): m/z calcd for C18H28NO3S+: 338.1790;
found: 338.1786.
13C NMR (125.8 MHz, CDCl3): δ = 22.2, 24.4, 24.6, 25.0, 25.6,
25.8, 33.3, 37.1, 37.2, 38.2 (10xCH2,Cy), 45.2 (CH2CAr), 55.4
(CArOCH3), 56.1 (NCHOCH3), 58.0 [C(CH2,Cy)5CH], 79.2
[C(CH2,Cy)5N], 98.5 (NCH), 112.7 (p-CHArCH2), 114.5 (o-
CHArOCH3), 121.3 (p-CHArOCH3), 129.9 (m-CHAr), 136.4
(CArCH2), 160.0 (CArOCH3), 170.6 (C=O).
(RS)-1-(4-Methoxy-2,2,5,5-tetramethyl-1,3-oxazolidin-3-yl)-3-
(3-methoxyphenyl)propan-1-one (3b)
Following GP A, dihydrooxazole 1e (254 mg, 2.00 mmol), 3-(3-
methoxyphenyl)propanoyl chloride (437 mg, 2.20 mmol), anhyd
MeOH (237 mg, 300 μL, 7.40 mmol), and anhyd Et3N (354 mg,
485 μL, 3.50 mmol) were used. The crude product was purified by
column chromatography (silica gel; n-hexane–EtOAc, 7:3); yield:
565 mg (88%); colorless, extremely viscous oil; Rf = 0.32 (n-hex-
ane–EtOAc, 7:3).
MS (CI, isobutane): m/z (%) = 404.5 (24, [MH]+), 372.5 (100, [MH
– CH4O]+).
HRMS (CI, isobutane): m/z calcd for C23H34NO3S+: 404.2259;
found: 404.2263.
IR (ATR): 2983, 2937, 2834, 1659, 1602, 1585, 1489, 1454, 1398,
1368, 1259, 1204, 1152, 1076, 1052, 1005, 900, 778, 696 cm–1.
(RS)-1-(4-Methoxy-2,2,5,5-tetramethyl-1,3-oxazolidin-3-yl)-2-
(3-methoxyphenyl)ethan-1-one (2i)
1H NMR (500.1 MHz, CDCl3): δ = 1.16, 1.33, 1.57, 1.61 [4 s, 12 H,
2 × C(CH3)2], 2.66–2.69 (m, 2 H, CH2CO), 2.97–3.02 (m, 2 H,
CH2CAr), 3.37 (s, 3 H, NCHOCH3), 3.79 (s, 3 H, CArOCH3), 4.51 (s,
Following GP A, dihydrooxazole 1e (320 mg, 2.52 mmol), 2-(3-
methoxyphenyl)acetyl chloride (511 mg, 2.77 mmol), anhyd
MeOH (299 mg, 378 μL, 9.32 mmol), and anhyd Et3N (446 mg,
611 μL, 4.41 mmol) were used. The crude product was purified by
column chromatography (silica gel; n-hexane–EtOAc, 7:3); yield:
518 mg (67%); yellow, extremely viscous oil; Rf = 0.21 (n-hexane–
EtOAc, 7:3).
3
4
1 H, NCH), 6.75 (dd, J = 8.3 Hz, J = 2.3 Hz, 1 H, p-CHArCH2),
4
3
6.78 (d, J = n.r., 1 H, o-CHArOCH3), 6.82 (d, J = 7.5 Hz, 1 H, p-
CHArOCH3), 7.21 (dd, 3J = 7.8 Hz, 3J = n.r., 1 H, m-CHAr).
13C NMR (125.8 MHz, CDCl3): δ = 22.9, 27.7, 27.8, 27.9 [2 ×
C(CH3)2], 31.4 (CH2CAr), 37.2 (CH2CO), 55.3 (CArOCH3), 56.9
(NCHOCH3), 81.8 [C(CH3)2CH], 94.2 (NCH), 95.5 [C(CH3)2N],
111.6 (p-CHArCH2), 114.4 (o-CHArOCH3), 120.9 (p-CHArOCH3),
129.7 (m-CHAr), 142.9 (CArCH2), 159.9 (CArOCH3), 171.0 (C=O).
IR (ATR): 2982, 2938, 2835, 1660, 1600, 1585, 1491, 1455, 1437,
1392, 1373, 1256, 1196, 1163, 1075, 1049, 1004, 902, 771, 715,
691 cm–1.
1H NMR (500.1 MHz, CDCl3): δ = 1.09, 1.33, 1.59, 1.63 [4 s, 12 H,
2 × C(CH3)2], 3.46 (s, 3 H, NCHOCH3), 3.72–3.72 (m, 2 H, CH2),
3.79 (s, 3 H, CArOCH3), 4.62 (s, 1 H, NCH), 6.79–6.85 (m, 3 H, p-
CHArCH2, o-CHArOCH3, p-CHArOCH3), 7.23–7.26 (m, 1 H, m-
CHAr).
13C NMR (125.8 MHz, CDCl3): δ = 22.9, 27.5, 27.5, 28.0 [2 ×
C(CH3)2], 43.0 (CH2), 55.3 (CArOCH3), 57.0 (NCHOCH3), 81.9
[C(CH3)2CH], 94.0 (NCH), 95.5 [C(CH3)2N], 112.6 (p-CHArCH2),
114.6 (o-CHArOCH3), 121.3 (p-CHArOCH3), 129.8 (m-CHAr), 136.3
(CH2CAr), 160.0 (CArOCH3), 170.0 (C=O).
MS (CI, isobutane): m/z (%) = 322.4 (66, [MH]+), 290.4 (100, [MH
– CH4O]+).
+
HRMS (CI, isobutane): m/z calcd for C18H28NO4 : 322.2018;
found: 322.2010.
Lactams 4 and 6; General Procedure B (GP B)
Under argon atmosphere, the respective methoxyamide (1 equiv),
dissolved in anhyd CH2Cl2 (10 mL per mmol amide), was added
dropwise to a suspension of AlCl3 (2.5 equiv) in anhyd CH2Cl2
(7 mL per mmol amide) at 0–5 °C. After stirring for 2 h at r.t., the
suspension was filtered. The filtrate was stirred overnight and then
poured into ice-water (17 mL per mmol imine). The phases were
separated and the aqueous phase was extracted with CH2Cl2
(3 × 20 mL per mmol imine). The combined organic phases were
washed with aq NaOH (2 × 8 mL per mmol amide, 2%), H2O
(1 × 8 mL per mmol amide), and dried (MgSO4). The solvent was
removed on a rotary evaporator. The crude product was purified as
described below for individual cases.
MS (CI, isobutane): m/z (%) = 308.2 (67, [MH]+), 276.2 (100, [MH
– CH4O]+).
+
HRMS (CI, isobutane): m/z calcd for C17H26NO4 : 308.1862;
found: 308.1855.
(RS)-1-(4-Methoxy-2,2,5,5-tetramethyl-1,3-thiazolidin-3-yl)-3-
(3-methoxyphenyl)propan-1-one (3a)
Following GP A, dihydrothiazole 1a (287 mg, 2.00 mmol), 3-(3-
methoxyphenyl)propanoyl chloride (437 mg, 2.20 mmol), anhyd
MeOH (237 mg, 300 μL, 7.40 mmol), and anhyd Et3N (354 mg,
485 μL, 3.50 mmol) were used. The crude product was purified by
column chromatography (silica gel; n-hexane–EtOAc, 4:1); yield:
359 mg (53%); colorless, extremely viscous oil; Rf = 0.38 (n-hex-
ane–EtOAc, 4:1).
(RS)-1,1,3,3-Tetramethyl-6,10b-dihydro-3H-[1,3]thiazolo[4,3-
a]isoquinolin-5-one (4a)
Following GP B, methoxyamide 2a (94 mg, 0.32 mmol) and AlCl3
(107 mg, 0.80 mmol) were used. The crude product was purified by
column chromatography (silica gel; n-hexane–MTBE, 7:3); yield:
20 mg (25%); colorless solid; mp 92–94 °C; Rf = 0.28 (n-hexane–
MTBE, 7:3).
IR (ATR): 2962, 2933, 2865, 2833, 1656, 1601, 1584, 1489, 1465,
1454, 1438, 1388, 1376, 1260, 1165, 1151, 1080, 1051, 919, 779,
697 cm–1.
1H NMR (500.1 MHz, CDCl3): δ = 1.36 [s, 6 H, C(CH3)2], 1.81,
1.91 [2 s, 6 H, C(CH3)2], 2.68–2.79 (m, 2 H, CH2CO), 2.96–2.99
(m, 2 H, CH2CAr), 3.39 (s, 3 H, NCHOCH3), 3.78 (s, 3 H,
CArOCH3), 4.82 (s, 1 H, NCH), 6.73–6.76 (m, 2 H, p-CHArCH2, o-
CHArOCH3), 6.79–6.80 (m, 1 H, p-CHArOCH3), 7.18–7.21 (m, 1 H,
m-CHAr).
13C NMR (125.8 MHz, CDCl3): δ = 23.4, 30.8, 30.9 [C(CH3)2],
31.7 (CH2CAr), 32.1 [C(CH3)2], 38.5 (CH2CO), 52.7 [C(CH3)2CH],
55.3 (CArOCH3), 56.0 (NCHOCH3), 72.7 [C(CH3)2N], 99.4 (NCH),
111.5 (p-CHArCH2), 114.4 (o-CHArOCH3), 120.9 (p-CHArOCH3),
129.7 (m-CHAr), 142.7 (CArCH2), 159.9 (CArOCH3), 171.5 (C=O).
IR (ATR): 3016, 2968, 2927, 2857, 1650, 1590, 1498, 1464, 1421,
1401, 1375, 1362, 1316, 1282, 1190, 1166, 1155, 1127, 760 cm–1.
1H NMR (500.1 MHz, CDCl3): δ = 1.20, 1.65, 1.81, 2.09 [4 s, 12 H,
4 × CH3], 3.56 (dd, 2J = 20.3 Hz, 5J = 1.3 Hz, 1 H, CH2), 3.85 (dd,
5
2J = 20.3 Hz, J = 2.0 Hz, 1 H, CH2), 4.98–4.99 (m, 1 H, NCH),
7.13–7.15 (m, 1 H, o-CHArCH2), 7.23–7.30 (m, 2 H, p-CHArCH2, p-
CHArCH), 7.34–7.36 (m, 1 H, o-CHArCH).
13C NMR (125.8 MHz, CDCl3): δ = 25.3, 26.6, 30.4, 32.2 (4 ×
CH3), 38.7 (CH2), 54.4 [C(CH3)2CH], 69.4 [C(CH3)2N], 72.7
(NCH), 125.8 (o-CHArCH), 126.5 (CHAr), 127.8 (o-CHArCH2),
128.1 (CHAr), 130.0 (CArCH), 132.4 (CArCH2), 167.1 (C=O).
MS (CI, isobutane): m/z (%) = 262.3 (100, [MH]+).
HRMS (CI, isobutane): m/z calcd for C15H20NOS+: 262.1266;
MS (CI, isobutane): m/z (%) = 338.3 (66, [MH]+), 306.2 (53, [MH
found: 262.1262.
– CH4O]+).
Synthesis 2013, 45, 355–364
© Georg Thieme Verlag Stuttgart · New York

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Synthesis of Tricyclic Lactams
361
(RS)-1-(4-Hydroxy-2,2,5,5-tetramethyl-1,3-thiazolidin-3-yl)-2-
phenylethan-1-one (5a)
By-product of 4a; yield: 29 mg (31%); colorless solid; mp 127–
128 °C; Rf = 0.13 (n-hexane–MTBE, 7:3).
(RS)-8-Methoxy-1,1,3,3-tetramethyl-6,10b-dihydro-3H-
[1,3]thiazolo[4,3-a]isoquinolin-5-one (4c)
Following GP B, methoxyamide 2c (102 mg, 0.32 mmol) and
AlCl3 (107 mg, 0.80 mmol) were used. Analysis of the crude prod-
uct by 1H NMR spectroscopy showed a single regioisomer. Purifi-
cation was not necessary; yield: 70 mg (75%); yellow solid; mp
139–140 °C.
IR (ATR): 3394, 2976, 2929, 1640, 1604, 1498, 1467, 1445, 1423,
1376, 1269, 1204, 1162, 1140, 1120, 1063, 745, 714, 697 cm–1.
1H NMR (500.1 MHz, CDCl3): δ = 1.24, 1.31, 1.87, 1.95 (4 s, 12 H,
IR (ATR): 3015, 2964, 2917, 2856, 2827, 1652, 1612, 1508, 1464,
1444, 1427, 1401, 1293, 1256, 1247, 1224, 1157, 1031, 833, 793
cm–1.
4 × CH3), 2.94 (d, 3J = 11.7 Hz, 1 H, OH), 3.86, 3.90 (2 d,
3
2J = 15.3 Hz, 2 H, CH2), 5.11 (d, J = 11.5 Hz, 1 H, NCH), 7.28–
7.29 (m, 3 H, 2 × o-CHAr, p-CHAr), 7.34–7.37 (m, 2 H, 2 × m-CHAr).
1H NMR (500.1 MHz, CDCl3): δ = 1.18, 1.62, 1.80, 2.07 [4 s, 12 H,
13C NMR (125.8 MHz, CDCl3): δ = 23.9, 29.5, 31.3, 31.9 (4 ×
CH3), 44.3 (CH2), 53.4 [C(CH3)2CH], 72.2 [C(CH3)2N], 92.4
(NCH), 127.1 (p-CHAr), 128.8, 128.9 (2 × o-CHAr, 2 × m-CHAr),
135.0 (CAr), 170.7 (C=O).
2
2 × C(CH3)2], 3.52 (dd, J = 20.4 Hz, 5J = 1.3 Hz, 1 H, CH2), 3.80
(s, 3 H, OCH3), 3.80–3.84 (m, 1 H, CH2), 4.92–4.93 (m, 1 H, NCH),
6.62 (d, 4J = 2.3 Hz, 1 H, o-CHArCH2), 6.80 (dd, 3J = 8.7 Hz,
4J = 2.5 Hz, 1 H, p-CHArCH2), 7.25 (d, 3J = 8.9 Hz, 1 H, m-
CHArOCH3).
13C NMR (125.8 MHz, CDCl3): δ = 25.1, 26.6, 30.4, 32.2 [2 ×
C(CH3)2], 38.9 (CH2), 54.3 [C(CH3)2CH], 55.4 (OCH3), 69.4
[C(CH3)2N], 72.3 (NCH), 111.6 (o-CHArCH2), 113.3 (p-CHArCH2),
122.3 (CArCH), 127.0 (m-CHArOCH3), 133.9 (CArCH2), 159.2
(CArOCH3), 167.0 (C=O).
MS (CI, isobutane): m/z (%) = 280.3 (95, [MH]+), 262.3 (100, [MH
– H2O]+).
HRMS (CI, isobutane): m/z calcd for C15H22NO2S+: 280.1371;
found: 280.1375.
(RS)-1,1,3,3,8-Pentamethyl-6,10b-dihydro-3H-[1,3]thiazo-
lo[4,3-a]isoquinolin-5-one (4b)
Following GP B, methoxyamide 2b (80 mg, 0.26 mmol) and AlCl3
(87 mg, 0.65 mmol) were used. Analysis of the crude product by 1H
NMR spectroscopy showed a single regioisomer. The crude product
was purified by column chromatography (silica gel; n-hexane–
MTBE, 7:3); yield: 26 mg (35%); colorless solid; mp 157–160 °C;
Rf = 0.30 (n-hexane–MTBE, 7:3).
MS (CI, isobutane): m/z (%) = 292.2 (100, [MH]+).
HRMS (CI, isobutane): m/z calcd for C16H22NO2S+: 292.1371;
found: 292.1364.
(RS)-1′,1′,8′-Trimethyl-6′,10b′-dihydrospiro[cyclohexane-1,3′-
thiazolo[4,3-a]isoquinolin]-5′-one (4d)
Following GP B, methoxyamide 2d (90 mg, 0.26 mmol) and AlCl3
(87 mg, 0.65 mmol) were used. Analysis of the crude product by 1H
NMR spectroscopy showed a single regioisomer. The crude product
was purified by column chromatography (silica gel; n-hexane–EtO-
Ac, 4:1); yield: 5 mg (8%); yellow, extremely viscous oil; Rf = 0.41
(n-hexane–EtOAc, 4:1).
IR (ATR): 2990, 2966, 2945, 2923, 2862, 1639, 1581, 1506, 1461,
1399, 1373, 1357, 1278, 1193, 1162, 1125, 944, 834, 787 cm–1.
1H NMR (500.1 MHz, CDCl3): δ = 1.19, 1.64, 1.80, 2.08 [4 s, 12 H,
2 × C(CH3)2], 2.33 (s, 3 H, CArCH3), 3.49–3.53 (m, 1 H, CH2), 3.78–
3.82 (m, 1 H, CH2), 4.95–4.96 (m, 1 H, NCH), 6.94–6.95 (m, 1 H,
o-CHArCH2), 7.04–7.06 (m, 1 H, p-CHArCH2), 7.23 (d, 3J = 8.0 Hz,
1 H, o-CHArCH).
13C NMR (125.8 MHz, CDCl3): δ = 21.1 (CArCH3), 25.2, 26.6,
30.4, 32.2 [2 × C(CH3)2], 38.7 (CH2), 54.3 [C(CH3)2CH], 69.4
[C(CH3)2N], 72.6 (NCH), 125.6 (o-CHArCH), 127.1 (CArCH), 127.4
(p-CHArCH2), 128.2 (o-CHArCH2), 132.3 (CArCH2), 137.9
(CArCH3), 167.1 (C=O).
IR (ATR): 2925, 2855, 1656, 1510, 1459, 1447, 1428, 1404, 1290,
1128, 904, 823, 784 cm–1.
1H NMR (500.1 MHz, CDCl3): δ = 1.15 [s, 3 H, C(CH3)2], 1.24–
1.31 (m, 1 H, CH2,Cy), 1.38–1.55 (m, 2 H, CH2,Cy), 1.60–1.64 (m,
1 H, CH2,Cy), 1.63 [s, 3 H, C(CH3)2], 1.75–1.87 (m, 3 H, CH2,Cy),
1.98–2.00 (m, 1 H, CH2,Cy), 2.33 (s, 3 H, CArCH3), 2.36–2.42, 3.45–
3.51 (2 m, 2 H, CH2,Cy), 3.50–3.54 (m, 1 H, CH2CAr), 3.82 (dd,
2J = 20.2 Hz, 5J = 2.2 Hz, 1 H, CH2CAr), 4.93–4.94 (m, 1 H, NCH),
6.94–6.95 (m, 1 H, o-CHArCH2), 7.04–7.05 (m, 1 H, p-CHArCH2),
7.21 (d, 3J = 8.0 Hz, 1 H, o-CHArCH).
MS (CI, isobutane): m/z (%) = 276.3 (100, [MH]+).
HRMS (CI, isobutane): m/z calcd for C16H22NOS+: 276.1422;
found: 276.1430.
13C NMR (125.8 MHz, CDCl3): δ = 21.1 (CArCH3), 24.1, 24.8 (2 ×
CH2,Cy), 25.2 [C(CH3)2], 26.1 (CH2,Cy), 26.7 [C(CH3)2], 37.6, 38.1
(2 × CH2,Cy), 39.3 (CH2CAr), 53.1 [C(CH3)2], 72.4 (NCH), 77.0
[C(CH2,Cy)5], 125.7 (o-CHArCH), 127.2 (CArCH), 127.4 (p-
CHArCH2), 128.1 (o-CHArCH2), 132.1 (CArCH2), 137.9 (CArCH3),
167.4 (C=O).
MS (CI, isobutane): m/z (%) = 316.3 (100, [MH]+).
HRMS (CI, isobutane): m/z calcd for C19H26NOS+: 316.1735;
(RS)-1-(4-Hydroxy-2,2,5,5-tetramethyl-1,3-thiazolidin-3-yl)-2-
(3-methylphenyl)ethan-1-one (5b)
By-product of 4b; yield: 32 mg (43%); yellow solid; mp 117–
119 °C; Rf = 0.15 (n-hexane–MTBE, 7:3).
IR (ATR): 3417, 2998, 2980, 2963, 2929, 2868, 1639, 1611, 1593,
1491, 1466, 1445, 1374, 1270, 1246, 1205, 1163, 1141, 1118, 1060,
884, 766, 722 cm–1.
1H NMR (500.1 MHz, CDCl3): δ = 1.24, 1.30, 1.85, 1.93 [4 s, 12 H,
found: 316.1738.
3
2 × C(CH3)2], 2.33 (s, 3 H, CArCH3), 2.83 (d, J = 11.8 Hz, 1 H,
OH), 3.80, 3.85 (2 d, 2J = 15.3 Hz, 2 H, CH2), 5.10 (d, 3J = 11.7 Hz,
1 H, NCH), 7.05–7.08 (m, 3 H, p-CHArCH2, o-CHArCH2, p-
CHArCH3), 7.20–7.23 (m, 1 H, m-CHAr).
(RS)-1-(3-Hydroxy-2,2-dimethyl-1-thia-4-azaspiro[4.5]decan-
4-yl)-2-(3-methylphenyl)ethan-1-one (5d)
By-product of 4d; yield: 31 mg (35%); colorless solid; mp 98–
100 °C; Rf = 0.21 (n-hexane–EtOAc, 4:1).
13C NMR (125.8 MHz, CDCl3): δ = 21.5 (CArCH3), 23.9, 29.6,
31.3, 31.9 [2 × C(CH3)2], 44.2 (CH2), 53.4 [C(CH3)2CH], 72.2
[C(CH3)2N], 92.4 (NCH), 125.8, 127.9 (2 × CHAr), 128.8 (m-CHAr),
129.6 (CHAr), 134.9 (CArCH2), 138.6 (CArCH3), 170.8 (C=O).
MS (CI, isobutane): m/z (%) = 294.3 (22, [MH]+).
HRMS (CI, isobutane): m/z calcd for C16H24NO2S+: 294.1528;
IR (ATR): 3269, 3014, 2984, 2926, 2858, 1625, 1607, 1589, 1487,
1448, 1404, 1373, 1180, 1167, 1154, 1134, 1077, 767, 720, 691
cm–1.
1H NMR (499.9 MHz, CDCl3): δ = 1.20 [s, 3 H, C(CH3)2], 1.17–
1.28 (m, 2 H, CH2,Cy), 1.29 [s, 3 H, C(CH3)2], 1.54–1.78 (m, 6 H,
3
CH2,Cy), 2.32 (s, 3 H, CArCH3), 2.85 (d, J = 11.7 Hz, 1 H, OH),
found: 294.1525.
2
3.00–3.12 (m, 2 H, CH2,Cy), 3.80 (d, J = 15.4 Hz, 1 H, CH2CAr),
2
3
3.84 (d, J = 15.3 Hz, 1 H, CH2CAr), 5.13 (d, J = 11.7 Hz, 1 H,
© Georg Thieme Verlag Stuttgart · New York
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362
T. Stalling, J. Martens
PAPER
NCH), 7.04–7.07 (m, 3 H, p-CHArCH2, o-CHArCH3, p-CHArCH3),
7.19–7.22 (m, 1 H, m-CHAr).
HRMS (CI, isobutane): m/z calcd for C19H26NO2S+: 332.1684;
found: 332.1676.
13C NMR (125.7 MHz, CDCl3): δ = 21.5 (CArCH3), 24.1 [C(CH3)2],
24.6, 25.4, 25.6 (3 × CH2,Cy), 29.8 [C(CH3)2], 36.7, 39.8 (2 ×
CH2,Cy), 44.9 (CH2CAr), 52.5 [C(CH3)2], 80.1 [C(CH2,Cy)5], 92.3
(NCH), 125.9, 127.8 (2xCHAr), 128.8 (m-CHAr), 129.6 (CHAr),
135.1 (CArCH2), 138.5 (CArCH3), 171.0 (C=O).
(RS)-8′-Methyl-6′,10b′-dihydro-5′H-dispiro[cyclohexane-1,1′-
thiazolo[4,3-a]isoquinoline-3′,1′′-cyclohexan]-5′-one (4g)
Following GP B, methoxyamide 2g (101 mg, 0.26 mmol) and
AlCl3 (87 mg, 0.65 mmol) were used. Analysis of the crude product
by 1H NMR spectroscopy showed a single regioisomer. The crude
product was purified by column chromatography (silica gel; n-hex-
ane–EtOAc, 4:1); yield: 34 mg (38%); colorless solid; mp 141–
142 °C; Rf = 0.45 (n-hexane–EtOAc, 4:1).
MS (CI, isobutane): m/z (%) = 334.4 (100, [MH]+), 316.3 (44, [MH
– H2O]+).
HRMS (CI, isobutane): m/z calcd for C19H28NO2S+: 334.1841;
found: 334.1835.
IR (ATR): 2927, 2849, 1656, 1617, 1590, 1509, 1448, 1424, 1402,
1287, 1264, 1246, 1219, 1188, 1172, 1130, 1119, 907, 830, 725
cm–1.
1H NMR (500.1 MHz, CDCl3): δ = 0.92–1.03 (m, 2 H, CH2,Cy),
1.21–1.42 (m, 2 H, CH2,Cy), 1.47–2.06 (m, 13 H, CH2,Cy), 2.13–2.19
(m, 1 H, CH2,Cy), 2.34 (s, 3 H, CH3), 3.44–3.48 (m, 1 H, CH2CAr),
3.45–3.51 (m, 1 H, CH2,Cy), 3.80–3.84 (m, 1 H, CH2CAr), 4.89–4.90
(m, 1 H, NCH), 6.93–6.94 (m, 1 H, o-CHArCH2), 7.04–7.06 (m,
1 H, p-CHArCH2), 7.13 (d, 3J = 8.0 Hz, 1 H, o-CHArCH).
13C NMR (125.8 MHz, CDCl3): δ = 21.2 (CH3), 22.2, 23.9, 25.0,
25.6, 25.7, 26.2, 31.2, 36.8, 38.2, 38.6 (10xCH2,Cy), 39.8 (CH2CAr),
61.5 [C(CH2,Cy)5CH], 72.7 (NCH), 77.0 [C(CH2,Cy)5N], 126.4
(CArCH), 127.0 (o-CHArCH), 127.1 (p-CHArCH2), 128.0 (o-
CHArCH2), 132.6 (CArCH2), 137.8 (CArCH3), 167.3 (C=O).
(RS)-8′-Methoxy-1′,1′-Dimethyl-6′,10b′-dihydrospiro[cyclo-
hexane-1,3′-thiazolo[4,3-a]isoquinolin]-5′-one (4e)
Following GP B, methoxyamide 2e (102 mg, 0.28 mmol) and
AlCl3 (94 mg, 0.70 mmol) were used. Analysis of the crude product
by 1H NMR spectroscopy showed a single regioisomer. Purification
was not necessary; yield: 92 mg (100%); yellow solid; mp 121–
123 °C.
IR (ATR): 2921, 2855, 1649, 1616, 1561, 1509, 1450, 1419, 1398,
1320, 1288, 1269, 1169, 1124, 1037, 861, 842, 824, 783, 739 cm–1.
1H NMR (500.1 MHz, CDCl3): δ = 1.13 [s, 3 H, C(CH3)2], 1.19–
1.28 (m, 1 H, CH2,Cy), 1.37–1.53 (m, 2 H, CH2,Cy), 1.58–1.60 (m,
1 H, CH2,Cy), 1.59 [s, 3 H, C(CH3)2], 1.73–1.85 (m, 3 H, CH2,Cy),
1.96–1.99, 2.35–2.41, 3.43–3.49 (3 m, 3 H, CH2,Cy), 3.49–3.53 (m,
1 H, CH2CAr), 3.78 (s, 3 H, OCH3), 3.82 (dd, 2J = 20.3 Hz,
5J = 2.3 Hz, 1 H, CH2CAr), 4.90–4.91 (m, 1 H, NCH), 6.61 (d,
MS (CI, isobutane): m/z (%) = 356.4 (100, [MH]+).
HRMS (CI, isobutane): m/z calcd for C22H30NOS+: 356.2048;
3
4
4J = 2.5 Hz, 1 H, o-CHArCH2), 6.78 (dd, J = 8.7 Hz, J = 2.6 Hz,
found: 356.2039.
1 H, p-CHArCH2), 7.22 (d, 3J = 8.7 Hz, 1 H, m-CHArOCH3).
(RS)-1-(15-Hydroxy-7-thia-14-azadispiro[5.1.58.26]pentadecan-
14-yl)-2-(3-methylphenyl)ethan-1-one (5g)
By-product of 4g; yield: 25 mg (27%); colorless, extremely viscous
oil; Rf = 0.30 (n-hexane–EtOAc, 4:1).
13C NMR (125.8 MHz, CDCl3): δ = 24.1, 24.8 (2 × CH2,Cy), 25.1
[C(CH3)2], 26.1 (CH2,Cy), 26.6 [C(CH3)2], 37.5, 38.0 (2 × CH2,Cy),
39.6 (CH2CAr), 53.0 [C(CH3)2], 55.4 (OCH3), 72.1 (NCH), 76.9
[C(CH2,Cy)5], 111.5 (o-CHArCH2), 113.2 (p-CHArCH2), 122.3
(CArCH), 127.1 (m-CHArOCH3), 133.6 (CArCH2), 159.1 (CArOCH3),
167.0 (C=O).
MS (CI, isobutane): m/z (%) = 332.2 (100, [MH]+).
HRMS (CI, isobutane): m/z calcd for C19H26NO2S+: 332.1684;
IR (ATR): 3379, 2926, 2855, 1628, 1590, 1489, 1448, 1374, 1267,
1252, 1178, 1108, 1072, 1027, 905, 763, 728, 692 cm–1.
1H NMR (500.1 MHz, CDCl3): δ = 1.15–1.38 (m, 6 H, CH2,Cy),
1.48–1.76 (m, 12 H, CH2,Cy), 2.32 (s, 3 H, CH3), 2.87 (d,
3J = 11.6 Hz, 1 H, OH), 2.98–3.04, 3.06–3.12 (2 m, 2 H, CH2,Cy),
2
3
found: 332.1675.
3.80, 3.85 (2 d, J = 15.3 Hz, 2 H, CH2CAr), 5.23 (d, J = 11.6 Hz,
1 H, NCH), 7.03–7.06 (m, 3 H, p-CHArCH2, o-CHArCH2, p-
CHArCH3), 7.19–7.22 (m, 1 H, m-CHAr).
(RS)-8′-Methoxy-3′,3′-Dimethyl-6′,10b′-dihydro-3′H,5′H-spi-
ro[cyclohexane-1,1′-thiazolo[4,3-a]isoquinolin]-5′-one (4f)
Following GP B, methoxyamide 2f (94 mg, 0.26 mmol) and AlCl3
(87 mg, 0.65 mmol) were used. Analysis of the crude product by 1H
NMR spectroscopy showed a single regioisomer. The crude product
was purified by column chromatography (silica gel; n-hexane–
EtOAc, 4:1); yield: 60 mg (69%); yellow solid; mp 126–127 °C;
Rf = 0.22 (n-hexane–EtOAc, 4:1).
13C NMR (125.8 MHz, CDCl3): δ = 21.5 (CH3), 22.2, 24.1, 24.5,
25.3, 25.5, 25.5, 33.6, 36.9, 37.1, 39.7 (10 × CH2,Cy), 44.8 (CH2CAr),
58.3 [C(CH2,Cy)5CH], 78.9 [C(CH2,Cy)5N], 90.7 (NCH), 125.8,
127.8 (2 × CHAr), 128.7 (m-CHAr), 129.5 (CHAr), 135.1 (CArCH2),
138.5 (CArCH3), 171.2 (C=O).
MS (CI, isobutane): m/z (%) = 374.5 (100, [MH]+), 356.4 (66, [MH
IR (ATR): 3013, 2996, 2971, 2933, 2920, 2859, 2841, 1655, 1613,
1590, 1505, 1464, 1444, 1417, 1290, 1265, 1238, 1227, 1130, 1039,
855, 837, 824 cm–1.
– H2O]+).
HRMS (CI, isobutane): m/z calcd for C22H32NO2S+: 374.2154;
found: 374.2148.
1H NMR (500.1 MHz, CDCl3): δ = 0.93–1.06 (m, 2 H, CH2,Cy),
1.20–1.29 (m, 1 H, CH2,Cy), 1.55–1.80 (m, 5 H, CH2,Cy), 1.76 [s,
3 H, C(CH3)2], 1.87–1.93, 1.97–2.00 (2 m, 2 H, CH2,Cy), 2.07 [s,
3 H, C(CH3)2], 3.44–3.48 (m, 1 H, CH2CAr), 3.80 (s, 3 H, OCH3),
(RS)-8′-Methoxy-6′,10b′-dihydro-5′H-dispiro[cyclohexane-
1,1′-thiazolo[4,3-a]isoquinoline-3′,1′′-cyclohexan]-5′-one (4h)
Following GP B, methoxyamide 2h (81 mg, 0.20 mmol) and AlCl3
(67 mg, 0.50 mmol) were used. Analysis of the crude product by 1H
NMR spectroscopy showed a single regioisomer. The crude product
was purified by column chromatography (silica gel; n-hexane–
MTBE, 7:3); yield: 63 mg (85%); colorless solid; mp 144–146 °C;
Rf = 0.18 (n-hexane–MTBE, 7:3).
2
5
3.80–3.85 (dd, J = n.r., J = 0.9 Hz, 1 H, CH2CAr), 4.88–4.89 (m,
1 H, NCH), 6.61 (d, 4J = 1.6 Hz, 1 H, o-CHArCH2), 6.80 (dd,
3J = 8.6 Hz, J = 2.3 Hz, 1 H, p-CHArCH2), 7.18 (d, J = 8.6 Hz,
4
3
1 H, m-CHArOCH3).
13C NMR (125.8 MHz, CDCl3): δ = 22.2, 25.7, 25.7 (3 × CH2,Cy),
31.0 [C(CH3)2], 31.2 (CH2,Cy), 32.4 [C(CH3)2], 36.8 (CH2,Cy), 39.3
(CH2CAr), 55.4 (OCH3), 63.2 [C(CH2,Cy)5], 69.5 [C(CH3)2], 72.5
(NCH), 111.6 (o-CHArCH2), 113.1 (p-CHArCH2), 121.3 (CArCH),
128.2 (m-CHArOCH3), 134.2 (CArCH2), 159.2 (CArOCH3), 166.9
(C=O).
IR (ATR): 2928, 2852, 1654, 1613, 1508, 1448, 1410, 1341, 1290,
1265, 1243, 1221, 1169, 1134, 1036, 906, 729 cm–1.
1H NMR (500.1 MHz, CDCl3): δ = 0.92–1.03 (m, 2 H, CH2,Cy),
1.20–1.41 (m, 2 H, CH2,Cy), 1.47–1.88 (m, 12 H, CH2,Cy), 1.94–
1.96, 2.02–2.05, 2.13–2.19 (3 m, 3 H, CH2,Cy), 3.44–3.48 (m, 1 H,
CH2CAr), 3.46–3.50 (m, 1 H, CH2,Cy), 3.80 (s, 3 H, OCH3), 3.84 (dd,
MS (CI, isobutane): m/z (%) = 332.4 (100, [MH]+).
Synthesis 2013, 45, 355–364
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Synthesis of Tricyclic Lactams
363
2J = 19.8 Hz, 5J = 1.0 Hz, 1 H, CH2CAr), 4.86–4.87 (m, 1 H, NCH),
6.62 (d, 4J = 2.3 Hz, 1 H, o-CHArCH2), 6.80 (dd, 3J = 8.6 Hz,
4J = 2.5 Hz, 1 H, p-CHArCH2), 7.15 (d, 3J = 8.6 Hz, 1 H, m-
CHArOCH3).
13C NMR (125.8 MHz, CDCl3): δ = 22.2, 23.9, 24.9, 25.6, 25.8,
26.1, 31.2, 36.7, 38.2, 38.6 (10 × CH2,Cy), 40.0 (CH2CAr), 55.4
(OCH3), 61.5 [C(CH2,Cy)5CH], 72.4 (NCH), 76.9 [C(CH2,Cy)5N],
111.5 (o-CHArCH2), 113.0 (p-CHArCH2), 121.5 (CArCH), 128.3 (m-
CHArOCH3), 134.2 (CArCH2), 159.2 (CArOCH3), 167.0 (C=O).
IR (ATR): 3067, 2983, 2967, 2928, 1634, 1610, 1506, 1462, 1446,
1404, 1338, 1291, 1253, 1208, 1190, 1174, 1156, 1112, 1038, 852,
833, 772 cm–1.
1H NMR (500.1 MHz, CDCl3): δ = 1.37, 1.42, 1.72, 1.89 [4 s, 12 H,
2 × C(CH3)2], 2.58–3.07 (m, 4 H, 2 × CH2), 3.78 (s, 3 H, OCH3),
4
4.84 (s, 1 H, NCH), 6.68 (d, J = 2.4 Hz, 1 H, o-CHArCH2), 6.71
(dd, 3J = 8.5 Hz, 4J = 2.6 Hz, 1 H, p-CHArCH2), 7.42–7.46 (m, 1 H,
m-CHArOCH3).
13C NMR (125.8 MHz, CDCl3): δ = 25.2, 30.1, 30.2, 30.2 [2 ×
C(CH3)2], 30.9 (CH2CAr), 39.0 (CH2CO), 51.0 [C(CH3)2CH], 55.3
(OCH3), 71.1 [C(CH3)2N], 73.8 (NCH), 110.8 (o-CHArCH2), 114.9
(p-CHArCH2), 125.1 (CArCH), 130.5 (m-CHArOCH3), 142.5
(CArCH2), 159.1 (CArOCH3), 171.6 (C=O).
MS (CI, isobutane): m/z (%) = 372.4 (100, [MH]+).
HRMS (CI, isobutane): m/z calcd for C22H30NO2S+: 372.1997;
found: 372.1999.
MS (CI, isobutane): m/z (%) = 306.3 (100, [MH]+).
HRMS (CI, isobutane): m/z calcd for C17H24NO2S+: 306.1528;
(RS)-8-Methoxy-1,1,3,3-tetramethyl-6,10b-dihydro-3H-[1,3]ox-
azolo[4,3]isoquinolin-5-one (4i)
Following GP B, methoxyamide 2i (111 mg, 0.36 mmol) and AlCl3
(120 mg, 0.90 mmol) were used. Analysis of the crude product by
1H NMR spectroscopy showed a single regioisomer. Purification
was not necessary; yield: 96 mg (97%); yellow solid; mp 133–
134 °C.
found: 306.1526.
(RS)-9-Methoxy-1,1,3,3-tetramethyl-1,6,7,11b-tetrahydro-
3H,5H-benzo[c]oxazolo[3,4-a]azepin-5-one (6b)
Following GP B, methoxyamide 3b (150 mg, 0.47 mmol) and
AlCl3 (156 mg, 1.17 mmol) were used. Analysis of the crude prod-
IR (ATR): 3077, 2987, 2963, 2938, 2839, 1654, 1612, 1593, 1510,
1463, 1451, 1436, 1401, 1373, 1257, 1245, 1213, 1201, 1169, 1035,
999, 945, 869, 829, 782 cm–1.
1H NMR (500.1 MHz, CDCl3): δ = 1.14, 1.61, 1.67, 1.76 [4 s, 12 H,
1
uct by H NMR spectroscopy showed a single regioisomer. The
crude product was purified by column chromatography (silica gel;
n-hexane–EtOAc, 7:3); yield: 136 mg (~100%); colorless, extreme-
ly viscous oil; Rf = 0.31 (n-hexane–EtOAc, 7:3).
2 × C(CH3)2], 3.56–3.66 (m, 2 H, CH2), 3.80 (s, 3 H, OCH3), 4.62–
4
4.63 (m, 1 H, NCH), 6.69 (d, J = 2.0 Hz, 1 H, o-CHArCH2), 6.80
IR (ATR): 2978, 2934, 2862, 2838, 1644, 1612, 1508, 1444, 1414,
1365, 1343, 1278, 1255, 1205, 1171, 1139, 1125, 1103, 1040, 1010,
908, 856, 731 cm–1.
(dd, 3J = 8.6 Hz, 4J = 2.4 Hz, 1 H, p-CHArCH2), 7.17 (d,
3J = 8.6 Hz, 1 H, m-CHArOCH3).
13C NMR (125.8 MHz, CDCl3): δ = 23.5, 26.7, 27.5, 28.2 [2 ×
C(CH3)2], 38.8 (CH2), 55.4 (OCH3), 65.7 (NCH), 81.0
[C(CH3)2CH], 92.7 [C(CH3)2N], 112.2 (o-CHArCH2), 113.1 (p-
CHArCH2), 122.9 (CArCH), 125.4 (m-CHArOCH3), 134.8 (CArCH2),
159.2 (CArOCH3), 165.7 (C=O).
1H NMR (500.1 MHz, CDCl3): δ = 0.91, 1.39, 1.60, 1.73 [4 s, 12 H,
2 × C(CH3)2], 2.46–2.51 (m, 1 H, CH2CO), 2.63–2.68 (m, 1 H,
CH2CAr), 2.75–2.80 (m, 1 H, CH2CO), 3.22–3.27 (m, 1 H, CH2CAr),
3.80 (s, 3 H, OCH3), 4.66 (s, 1 H, NCH), 6.66 (d, 4J = 2.7 Hz, 1 H,
3
4
o-CHArCH2), 6.75 (dd, J = 8.6 Hz, J = 2.7 Hz, 1 H, p-CHArCH2),
7.13 (d, 3J = 8.6 Hz, 1 H, m-CHArOCH3).
MS (CI, isobutane): m/z (%) = 276.2 (100, [MH]+).
13C NMR (125.8 MHz, CDCl3): δ = 22.7, 26.2, 26.9, 27.7 [2 ×
C(CH3)2], 31.7 (CH2CAr), 39.5 (CH2CO), 55.4 (OCH3), 69.9
(NCH), 82.8 [C(CH3)2CH], 93.7 [C(CH3)2N], 111.5 (o-CHArCH2),
114.9 (p-CHArCH2), 124.3 (CArCH), 130.0 (m-CHArOCH3), 142.9
(CArCH2), 158.6 (CArOCH3), 173.1 (C=O).
+
HRMS (CI, isobutane): m/z calcd for C16H22NO3 : 276.1600;
found: 276.1602.
Crystal Data of 4i
Data collection was performed at 153(2) K on a Bruker Kappa Apex
II CCD diffractometer, using MoKα radiation. C16H21NO3,
Mr = 275.34, λ = 0.71073 Ǻ, orthorhombic, space group Pbcn, unit
MS (CI, isobutane): m/z (%) = 290.2 (100, [MH]+).
+
HRMS (CI, isobutane): m/z calcd for C17H24NO3 : 290.1756;
cell
dimensions:
a = 30.1103(6) Å,
b = 8.4760(2) Å,
c = 11.3052(2) Å, α = 90°, β = 90°, γ = 90°, V = 2885.26(10) Å3,
Z = 8, DC = 1.268 Mg/m3, absorption coefficient = 0.087 mm–1,
F(000) = 1184, reflections collected 57332, independent reflections
4226 (Rint = 0.0757). Reflections were collected over the range
3.08° < 2θ < 30.11°, index ranges: –42 < h < 42; –11 < k < 7; –15 <
l < 15, completeness to θ = 30.11° is 99.7%. To solve the crystal
structure, the SHELXS-97 program was used and for least-squares
refinement on F2 the SHELXL-97 program, respectively. Non-hy-
drogen atoms were refined with anisotropic displacement parame-
ters. All H atoms were placed in calculated positions and refined
using a riding model. 4226 reflections were included in calculation,
giving final standard residual R1 value of 0.0476 (ωR2 = 0.1154) for
observed data [I > 2σ(I)] and 0.0674 for all data (ωR2 = 0.1273)
(data/restraints/parameters = 4226:0:186). Largest diff. peak hole
0.374 and –0.242 e/Ǻ3. The goodness-of-fit on F2 was 1.064.
found: 290.1759.
Acknowledgment
The silica gel was generously supplied to us by Grace GmbH & Co.
KG. T. S. gratefully acknowledges the Heinz-Neumüller-Stiftung
for a doctoral fellowship. We thank W. Saak and D. Haase for
X-ray crystallography.
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 355–364

364
T. Stalling, J. Martens
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© Georg Thieme Verlag Stuttgart · New York