Angularly substituted octahydroindoles, decahydroquinolines, octahydropyrindines, and octahydrocyclopenta[b]pyrroles by Bruylants reaction

Article abstract of DOI:10.1007/s00706-003-0136-8

The easily available cycloalkanoyl acetic- and propionic acid esters are transformed to the corresponding amines by standard procedures. These in turn provided an efficient access to cyclic α-aminonitriles, which were reacted with a series of Grignard reagents yielding stereoselectively the cis-configured title compounds; the scope and limitation of this route were investigated. The stereochemical assignment was achieved by X-ray crystallography and NMR spectroscopy. Springer-Verlag 2004.

Full text of DOI:10.1007/s00706-003-0136-8

Monatshefte f€ur Chemie 135, 557–579 (2004)
DOI 10.1007/s00706-003-0136-8
Angularly Substituted Octahydroindoles,
Decahydroquinolines, Octahydropyrindines,
and Octahydrocyclopenta[b]pyrroles
by Bruylants Reaction
Eberhard Reimann , Christian Ettmayra, and Kurt Polborn
ꢀ
€
Department Pharmazie – Zentrum fur Pharmaforschung,
€
€
Ludwig-Maximilians-Universitat Munchen, D-81377 Munchen, Germany
€
Received October 22, 2003; accepted October 27, 2003
Published online February 5, 2004 # Springer-Verlag 2004
Summary. The easily available cycloalkanoyl acetic- and propionic acid esters are transformed to the
corresponding amines by standard procedures. These in turn provided an efficient access to cyclic
ꢀ-aminonitriles, which were reacted with a series of Grignard reagents yielding stereoselectively the
cis-configured title compounds; the scope and limitation of this route were investigated. The stereo-
chemical assignment was achieved by X-ray crystallography and NMR spectroscopy.
Keywords. Intramolecular Strecker reaction; X-Ray structure determination; Angularly substituted
N-heterocycles.
Introduction
The phenyl cyclohexyl-amine-fragment forms part of several remarkable sub-
stances possessing highly potent activity on central nervous system. Perhaps the
best known example is phencyclidine (PCP), which has been developed in the
1950s as an intravenous anaesthetic but, due to the serious side effects, its use
was stopped, but until today it is abused as a dangerous psychotomimetikum [1, 2]
(Fig. 1, I).
The search for PCP replacements soon after led to the structural analogue
ketamine II which proved to be a strong analgesic and, because of its rapid anaes-
thetic onset after injection, it has found increased use in the induction of anesthesia
and in the emergency surgery. But hallucinatory side effects particularly occurring
in the post-narcotic stage have been also reported [3, 4]. Furthermore, a series of
ꢀ
Corresponding author. E-mail: ebrei@cup.uni-muenchen.de
a
€
Part of PhD thesis, LMU Munchen, D

558
E. Reimann et al.
Fig. 1. Compounds with an integrated phenylcyclohexylamine framework
more complex structures obviously connected to the search for PCP analogues
contain a rigid aryl cyclohexylamine framework, e.g. the angularly arylated hydro-
indoles and -quinolines 15 and 16 (Fig. 1, R1 ¼ H), which are claimed to exhibit
also CNS depressant properties similar to those attributed to PCP. Unfortunately,
detailed pharmacological data are not available hitherto [5].
The title compounds attracted our interest not only because of their biological
activities mentioned; they also suggest to be appropriate precursors for the construc-
tion of the frameworks of the erythrina and schelhammerane alkaloids (Fig. 1, III,
IV) since they differ from title compound 15 only by the C2- or C3-bridge connecting
the nitrogen- and the carbon atom C-12 of the aryl moiety. Thus in connection with
our investigations relating to the intramolecular alkylation of aromatic compounds,
we wish to report in this paper a general stereoselective approach to the title
compounds 15–18 as well as to check its scope and limitations.
Results and Discussion
The first synthesis of the compounds like 15 and 16 (Fig. 1, R1 ¼ H) – being the
only one to our knowledge – was based on partially hydrogenated indoles and
quinolines, each involving an intact bridgehead imino moiety. The angular substi-
tuents were introduced by addition of aryllithium compounds or in a two step route
by formation of the ꢀ-aminocarbonitriles followed by replacement of the nitrile
group by the corresponding Grignard reagents known as Bruylants reaction [6].
Unfortunately, the total yields of the compounds reported were unsatisfactory or
given not at all. Furthermore, no information concerning the stereochemistry of the
bicyclic frameworks had been reported [5]. This gave rise to a more detailed
investigation in this field described in the present work.
Following the Bruylants strategy mentioned above, at first we focused our
interest on the preparation of the bicyclic ꢀ-aminonitriles 11–14, which could
be prepared in excellent yields by intramolecular Strecker reaction using the O-
protected aminoketones 9 and 10 to afford the perhydrogenated indole-, quinoline-,
pyrindine-, and cyclopenta[b]pyrrole-carbonitriles 11, 12a, 13, and 14. Compound
12b was prepared starting from nitrile 19b via the amine 9g, whereas 9f failed to
give the corresponding aminonitrile (Scheme 3, A). The educts 9 and 10 in turn
were easily available starting from the known cycloalkanone acid esters 1 and 2
[7–9] and further transformation by standard procedures via 3 ! 8 (see Schemes 1
and 2).
Concerning the stereochemistry, 12a, 12b, and 14 only showed a single set
of lines in the NMR spectra indicating a stereoselective formation of the possible

Angularly Substituted Perhydro N-Heterocycles by Bruylants Reaction
559
Scheme 1
cis- or trans-fused heterocycles, whereas the produtcs 11a–11d and 13 were found
to be diastereomeric mixtures unseparable by TLC. Due to an additional chirality
center located at the N-substituent compound 11c exhibited four sets of signals in
the 13C NMR spectrum. The ratios of the diastereomers were determined using the
integrals of the 1H NMR absorptions originating from the corresponding N-methyl-
or benzyl groups.

560
E. Reimann et al.
Scheme 2
The configuration of compounds 12a and 12b as well as 14 could be assigned
comparing appropriate NMR data, namely the 13Cꢁ-values of the tertiary bridge-
head atom, with those of known closely related compounds. Thus, the carbon
atoms concerned resonates in trans-decaline-4a-carbonitrile [10] or in a more com-
plex structure containing the trans configured unit of 12 [11] at ꢁ ¼ 44.8 and
44.5 ppm. These results matched very well with those observed for 12a and 12b
(ꢁ ¼ 44.94 and 44.35 ppm, Scheme 1) indicating the trans-configuration of the
products.
Angularly substituted carbonitriles of type 14 obviously have not yet been
reported until now. NMR Data published concerning the stereochemistry exclu-
sively refer to cis-configured bicyclo[3.3.0]octanes, corresponding values for trans-
fused compounds are lacking [12]. Therefore the assignment of 14 was based on
the downfield shift of about 6–8 ppm induced by angular substituents, e.g. methyl
or carboxyl, on the neighbouring bridgehead carbon atom of the cis-fused parent
bicyclooctane (ꢁC-ang ¼ 43.2 ppm vs. ꢁC-6a ¼ 50.9 or 49.8 ppm) [12]. In addition, the
C-3a atom of a more complex structure containing the cis-fused cyclopentapyrrole
framework resonates at ꢁ ¼ 50.4 ppm [13]. The value ꢁC-3a ¼ 50.94 ppm found for
14 is in line with the reported ones proving the cis-fused framework of the product.
In the same manner the configurations of compounds 11 and 13 could be
assigned, since both stereomers were available. In the perhydroindoles 11 the
inversion from the trans- to the cis-fused ring system caused an upfield shift of
about 5 ppm at carbon atom C-3a comparable with those observed at C-4a in N-
methyldecahydroquinolines [14–17]. On the other hand the corresponding bridge-
head carbon atom C-4a of the pyrindine derivative 13 exhibited a somewhat
smaller difference (Dꢁ ¼ 3.2 ppm, Scheme 1). In this connection it should be noted,
that the oily product 13 solidified after some time. The NMR spectrum of the
crystals measured immediately after their dissolution indicated only the trans-
stereomer, after about 3 hours a 1:1-mixture of both stereomers could be observed,
and after several further hours, a stable 2:1-equilibrium was reached revealing the
cis-configured compound as the main stereomer. Compounds 11 gave the same
cis=trans ratios.

Angularly Substituted Perhydro N-Heterocycles by Bruylants Reaction
561
Scheme 3
In the final step the nitriles 11–14 were reacted with a number of Grignard
reagents according to Bruylants giving the new title compounds 15–18 (Scheme 1).
Using aryl Grignard reagents the yields of the products 15a–15f and 16b and 16c
were low (11–34%) with the exception of 18 and 17b, which were formed with
78% or only in traces (0.2%). Reacting the secondary base 12b with Grignard
reagents no products were observed (Scheme 3, B). Changing the experimental
procedure, e.g. inverse order of addition of the reagents, variation of the tempera-
ture and the reaction time as well as the halogen of the Grignard reagent did not
improve the result. Byproducts, e.g. enamines and their hydrolysis products which
were reported to be formed during the Bruylants reaction [18], or arylketones
formed by addition to the nitrile function were not observed. The ketone 21, how-
ever, could be obtained when the educt 11a was reacted with phenyl lithium
(Scheme 4).
The low yields obtained suggested, that the reaction rate depended on the steric
bulk of both the Grignard reagent and the N-substituent of the educts. Indeed
support of this assumption was best seen by reacting phenyl magnesium bromide
with N-benzylated and N-methylated educts 11a and 11b yielding 25 and 34% of
15a and 15f, whereas bulky N-substituents, e.g. 1-phenylethyl or isopropyl in the
educts 11c and 11d, were found to inhibit the desired conversion completely. In
contrast, replacement of aryl Grignard reagents by those possessing a smaller steric
demand at the reaction center provided high yields of the products. Thus, reacting
the educts 11a and 11b with benzyl- and methyl Grignard reagents, 15k, 15l, 16a,
and 17a were obtained in 76–83% yields. Even the same was true for the educts
11c and 11d giving also moderate to satisfactory yields of products 15g, 15h, and
15i (Scheme 1).
NMR Spectroscopy of the target compounds 15–18 indicated them all to be
single diastereomers independent of the stereochemical property and purity of the
educts 11–14 signifying that the Bruylants reaction had diastereoselectively
occured. Since an unequivocal stereochemical assignment of the octahydroindoles
15 failed by NMR, an X-ray diffraction analysis of compound 15a was performed
showing a cis-fused hydroindole framework and the aryl group axially attached to
the carbocyclus (Fig. 2). The true configuration of 15a now also enabled the stereo-
chemical assignment of the analogous compounds 15b–15f including the N-
regioisomer pyrindine 17b, using the same reasoning described above for the

562
E. Reimann et al.
Fig. 2. Crystal structure of 15a
educts 11–14. Thus, the 13Cꢁ values of the bridgehead carbon atom C-3a of the
products 15b–15f as well as of C-4a of 17b were found to be in good accordance
with that available from 15a (ꢁ ¼ 45.58–47.16 vs. 46.67 ppm, Scheme 1 and Exp.)
indicating also the cis-configuration of the compounds concerned.
The cis-configuration of the angular methyl derivatives 15i and 15k was proved
by comparison with a known compound. Their hydrogenolysis afforded the same
deprotected amine 15m (Scheme 4), exhibiting 1Hꢁ-values, which were completely
in line with those of the identical cis-configured product reported in Ref. [21]. In
addition, the 13Cꢁ values of the bridgehead carbon atom C-3a of 15i, 15k, and 15m
now were available resonating between ꢁ ¼ 44.18 and 45.06 ppm (Scheme 1 and
Exp.).
In a similar manner the configurations of the quinoline derivatives 16b and 16c
were established by way of debenzylated product 16e (Scheme 2). The NMR data
Scheme 4

Angularly Substituted Perhydro N-Heterocycles by Bruylants Reaction
563
found, namely the ꢁ-value of the carbon atom C-4a were in line with those
reported for the known cis-8a-phenyldecahydroquinoline [19] (ꢁC-4a ¼ 35.90 vs.
35.70 ppm). In contrast, the corresponding absorptions of the N-benzylated com-
pounds 16b and 16c were found at lower field (ꢁC-4a ¼ 42.19 and 42.22 ppm,
Scheme 1).
The cis-configuration of the angularly substituted benzyl-indoles 15g, 15i, and
15l, as well as 16a, and 17a was assigned by a significant NOE between the
bridgehead methin proton and one of the protons of the angular benzyl group
attached either to the methylene group or to the ortho position of the aryl moiety.
In the case of 16a and 17a the hydrochlorides of the N-deprotected compounds 16d
and 17c were prepared providing more distinct results than the educts (Scheme 2).
In addition it should be noted that a small amount of the trans-configured stereo-
mer 16b could be separated (Exp.). For comparison purposes the corresponding
13Cꢁ values of the bridgehead methin carbon atom now available are also presented
in Scheme 1.
The assignment of the stereochemistry of the cyclopentanopyrrole 18 by NOE
failed because of unseparable superimpositions of the peaks of the methin proton.
But due to the similar absorption of C-3a in 14 as well as to that of the reference
compound mentioned above [11] the cis-configuration could be assumed.
The highly stereoselective course of the syntheses of the target compounds may
be explained on the basis of the reported mechanism of the Bruylants reaction [20].
In the first step the Grignard reagent coordinates with the nitrogen atoms of the ꢀ-
aminonitrile as shown in Scheme 5 (V) followed by the formation of an intermedi-
ate iminium salt with a preferred puckered ringfusion. The subsequent nucleophilic
attack of the Grignard reagent is favored from the re-face of the carbon-nitrogen
double bond (VI ! VII). Finally it should be noted that the presence of the cyanide
group in the intermediate seems to play an important role concerning the stereo-
selective course of the reaction, since the preparation of 15k gave a stereomeric
mixture when the corresponding pure N-benzylhexahydroindolium bromide was
used as educt [21].
In conclusion, we have established a general, stereoselective route to the title
compounds. The dominant features consist of the initial intramolecular Strecker
reaction followed by the Bruylants reaction. We are currently investigating this
pathway in further detail and applying the procedure to natural product and drug
synthesis.
Scheme 5

564
E. Reimann et al.
Experimental
Melting points are measured with a Reichert hot-stage microscope and are uncorrected. IR: Perkin
Elmer FT-IR Paragon 1000 and Jasco FT-IR 410. NMR: Jeol GSX 400 and Jeol GSX 500 (1H: 400 and
13
500 MHz, C: 100 and 125 MHz, CDCl3, TMS as internal reference), t ¼ 25ꢁC (unless otherwise
stated); MS (70 eV): Hewlett Packard MS-Engine. Elemental analyses: Heraeus CHN-Rapid and
Elementar Vario EL; the results are in good agreement with the calculated values. Thin layer chro-
matography (TLC): aluminum sheets Kieselgel 60 F254 (Merck) and aluminum sheets Aluminiumoxid
F254 (Fluka), each thickness of layer 0.2 mm. Flash chromatography (FC): ICN-Sili Tech 32–63, 60 A
and Aluminiumoxid Typ 507 C neutral 0.05–0.15 mm. (Oxocycloalkyl)alkanoic acid ethyl esters 1 and
2 were prepared according to literature: 1a=Ref. [7], 2b=Ref. [8], 1b and 2a=Ref. [9].
Improved General Procedure for the Synthesis of Dioxolanes
3 and 4 According to Ref. [22]
A solution of the corresponding cycloalkanone 1 or 2, ethane-1,2-diol, and pyridinium tosylate (PPTS)
in 300 cm3 of benzene was refluxed with water separation by a Dean-Stark trap until the reaction was
completed (about 5 h; IR monitoring). After evaporating the solvent in vacuo the residue was dissolved
in 150 cm3 of Et2O and the solution was consecutively washed with 4ꢂ100 cm3 of H2O, 100 cm3 of
saturated NaHCO3 solution, 100 cm3 of brine, and dried (Na2SO4). The solvent was removed under
reduced pressure to give sufficiently pure products for the next step.
(1,4-Dioxaspiro[4.5]dec-6-yl)acetic acid ethyl ester (3a)
1a 54.5g (296mmol), ethane-1,2-diol 91.8g (1.48 mol), PPTS 22.3g (89.2 mmol); yield 66.8g (99%)
colourless oil, bp 96ꢁC=19 Pa (Ref. [23] 106–109ꢁC=66 Pa); TLC (CH2Cl2): Rf ¼ 0.40; IR (film):
ꢂꢀ¼ 1736 (CO2R) cmꢃ1; MS (CI): m=z (%) ¼ 229 (Mþꢄþ1, 10), 183 (Mþꢄ –C2H5O, 100), 155 (14),
1
99 (5); H NMR: ꢁ ¼ 4.05 (dq, J ¼ 7.1, 1.8 Hz, CO2CH2), 3.90–3.81 (m, OCH2CH2O), 2.47 (dd,
J ¼ 14.9, 5.6Hz, 1H, CH2CO2), 2.19–2.10 (m, CH), 1.99 (dd, J ¼ 14.9, 7.9 Hz, 1H, CH2CO2),
1.74–1.68 and 1.61–1.52 (2m, each 2H), 1.47–1.35 (m, 1H), 1.35–1.21 (m, 3H), 1.18 (t, J ¼ 7.1 Hz,
CH3) ppm.
3-(1,4-Dioxaspiro[4.5]dec-6-yl)propionic acid methyl ester (3b)
1b 50.0g (272mmol), ethane-1,2-diol 84.2 g (1.36mol), PPTS 20.4 g (81.6mmol); yield 60.1 g (97%)
colourless oil, bp 101–108ꢁC=57 Pa (Ref. [24] 110–130ꢁC=66Pa); IR (film): ꢂꢀ¼ 1739 (CO2R) cmꢃ1
;
MS (EI): m=z (%) ¼ 228 (Mþꢄ, 10), 183 (32), 155 (9), 113 (25), 99 (100), 55 (28); 1H NMR data are in
line with those published in Ref. [25]; 13C NMR: ꢁ ¼ 174.23, 110.35, 64.51, 64.35, 51.20, 43.80, 34.37,
33.98, 28.29, 24.29, 23.63, 23.52 ppm.
3-(1,4-Dioxaspiro[4.4]non-6-yl)propionic acid methyl ester (4a)
2a 52.0 g (306 mmol), ethane-1,2-diol 94.8 g (1.53 mol), PPTS 25.5 g (102 mmol); yield 64.83 (99%)
colourless oil; TLC (CH2Cl2): Rf ¼ 0.40; IR (film): ꢂꢀ¼ 1738 (CO2R) cmꢃ1; MS (EI): m=z (%) ¼ 214
(Mþꢄ, 15), 183 (10), 141 (17), 125 (11), 99 (100); 1H NMR data are in line with those published in Ref.
[26]; 13C NMR: ꢁ ¼ 174.24, 117.95, 64.58, 64.42, 51.46, 45.45, 35.71, 32.82, 29.31, 24.38, 20.63 ppm.
(1,4-Dioxaspiro[4.4]non-6-yl)acetic acid methyl ester (4b)
2b 43.5g (278 mmol), ethane-1,2-diol 86.4g (1.39 mol), PPTS 20.9g (83.6 mmol); yield 66.8g
(99%) colourless oil, bp 68ꢁC=5.7Pa; TLC (CH2Cl2:MeOH¼ 10:1): Rf ¼ 0.62; IR (film): ꢂꢀ¼ 1737

Angularly Substituted Perhydro N-Heterocycles by Bruylants Reaction
565
(CO2R) cmꢃ1; MS (CI): m=z (%) ¼ 169 (Mþꢄ –CH3O, 100), 125 (59), 99 (20); 1H NMR: ꢁ ¼ 3.94–3.83
(m, OCH2CH2O), 3.66 (s, OCH3), 2.48 (dd, J ¼ 14.8, 5.9 Hz, 1H, CH2CO2), 2.47–2.37 (m, CH), 2.23
(dd, J ¼ 14.8, 8.1 Hz, 1H, CH2CO2), 2.00 (ddt, J ¼ 12.6, 7.8, 4.5 Hz, 1H), 1.80–1.74 (m, 2H), 1.74–
1.61 (m, 2H), 1.45–1.35 (m, 1H) ppm; 13C NMR: ꢁ ¼ 173.71, 117.68, 64.67 (2C), 51.44, 42.60, 35.12,
34.32, 29.44, 20.51 ppm.
General Procedure for the Synthesis of (Dioxaspiroalkyl)alkanoic acids
5 and 6 According to Ref. [27]
The mixture of the corresponding ester 3 or 4, KOH=H2O, and EtOH was refluxed for 2 h. After
addition of 6 N H2SO4 with ice-cooling the solution was saturated with NaCl and extracted with
3ꢂ100 cm3 of Et2O. The combined organic extracts were washed with 100 cm3 of brine and dried
(Na2SO4). After removing the solvent in vacuo, the remaining colourless or light yellow oils were used
for the next step without further purification.
(1,4-Dioxaspiro[4.5]dec-6-yl)acetic acid (5a)
3a 58.8g (257mmol), KOH 23.2g (407 mmol)=H2O 60cm3, EtOH 60 cm3, 6 N H2SO4 54.8cm3; yield
49.86 g (97%), bp 128–131ꢁC=7.8 Pa (Ref. [27] 123ꢁC=2.7 Pa), the product crystallized when it was
stored in the refrigerator, mp 54ꢁC (Ref. [23] 54–56ꢁC); IR (film): ꢂꢀ¼ 3650–2360 (OH), 1704 (C¼O)
cmꢃ1; MS (CI): m=z (%) ¼ 201 (Mþꢄþ1, 100), 183 (29), 139 (23); 1H NMR: ꢁ ¼ 9.81 (broad s, CO2H),
3.92–3.83 (m, OCH2CH2O), 2.53 and 2.05 (2dd, J ¼ 15.2, 5.8 and 15.2, 7.4 Hz, each 1H, CH2CO2),
2.19–2.11 (m, CH), 1.76–1.70 and 1.62–1.55 (2m, each 2H), 1.47–1.18 (m, 4H) ppm; 13C NMR:
ꢁ ¼ 179.57, 109.84, 64.68, 64.49, 41.53, 34.36, 34.25, 30.07, 24.60, 23.64 ppm.
3-(1,4-Dioxaspiro[4.5]dec-6-yl)propionic acid (5b)
3b 42.1g (184 mmol), KOH 16.6 g (296 mmol)=H2O 70 cm3, EtOH 70cm3, 6 N H2SO4 39.2cm3; yield
37.43 g (97%); IR (film): ꢂꢀ¼ 3650–2355 (OH), 1710 (C¼O) cmꢃ1; MS (CI): m=z (%) ¼ 215 (Mþꢄþ1,
1
100), 197 (51), 153 (58); H NMR data were in line with those published in Ref. [24].
3-(1,4-Dioxaspiro[4.4]non-6-yl)propionic acid (6a, C10H16O4)
4a 39.0g (182mmol), KOH 16.6g (296 mmol)=H2O 70cm3, EtOH 70 cm3, 6 N H2SO4 38.8cm3; yield
33.12 g (91%, purification of the crude product failed); TLC (CH2Cl2:MeOH¼ 10:0.2): Rf ¼ 0.42; IR
(film): ꢂꢀ¼ 3650–2250 (OH), 1710 (C¼O) cmꢃ1; MS (CI): m=z (%) ¼ 201 (Mþꢄþ1, 96), 183 (90), 139
1
(100); H NMR: ꢁ ¼ 10.41 (broad s, CO2H), 4.98–3.83 (m, OCH2CH2O), 2.42–2.32 (m, 2H), 1.80–
1.52 (m, 8H), 1.40–1.29 (m, 1H) ppm; 13C NMR: ꢁ ¼ 179.91, 117.97, 64.53, 64.40, 45.25, 35.69,
32.70, 29.29, 24.04, 20.61 ppm.
(1,4-Dioxaspiro[4.4]non-6-yl)acetic acid (6b, C9H14O4)
4b 18.21 g (91.1mmol), KOH 8.21 g (144 mmol)=H2O 45cm3, EtOH 45cm3, 6 N H2SO4
19.4cm3; yield 15.17 g (90%, purification of the crude product failed); IR (film): ꢂꢀ¼ 3650–2360
1
(OH), 1708 (C¼O) cmꢃ1; MS (CI): m=z (%) ¼ 188 (Mþꢄþ1, 2), 183 (67), 139 (100); H NMR:
ꢁ ¼ 3.97–3.85 (m, OCH2CH2O), 2.53 and 2.28 (2dd, J ¼ 15.5, 5.8 and 15.5, 8.2 Hz, each 1H,
CH2CO2), 2.48–2.35 (m, CH), 2.09–1.97 (m, 1H), 1.82–1.73 and 1.73–1.61 (2m, each 2H), 1.47–
1.37 (m, 1H) ppm.

566
E. Reimann et al.
General Procedure for the Synthesis of Amides 7 and 8
A mixture of the acid 5 or 6 and N,N0-carbonyldiimidazole (CDI) in anhydrous THF was stirred until
generation of CO2 was completed (ca. 30min). Then the amine was added and the solution was refluxed
for 8 h. After evaporating the solvent in vacuo the residue was dissolved in 200 cm3 of CH2Cl2 and the
solution was consecutively washed with 3ꢂ100 cm3 of H2O, 100cm3 of 1 N HCl and 2ꢂ250 cm3 of
saturated Na2CO3 solution. After drying with Na2SO4 and removing the solvent invacuo the residue was
crystallized from Et2O and finally washed with a small volume of ice-cold Et2O. If the product did not
crystallize or further product could not be obtained from the mother liquor, the solvent was evaporated
under reduced pressure and the residue purified by FC (eluents are the same as described under TLC).
N-Benzyl-2-(1,4-dioxaspiro[4.5]dec-6-yl)acetamide (7a, C17H23NO3)
5a 32.8g (164 mmol), CDI 26.0 g (160mmol), benzylamine 22.8g (328mmol), THF 350 cm3; yield
38.4g (81%) colourless crystals, mp 110ꢁC; TLC (CH2Cl2:MeOH¼ 10:0.3): Rf ¼ 0.36; IR (KBr):
ꢂꢀ¼ 3343 (NH), 1639, 1570, and 1496 (CONH) cmꢃ1; MS (EI): m=z (%) ¼ 289 (Mþꢄ, 14), 244
1
(18), 155 (37), 106 (22), 99 (100), 91 (54), 55 (37); H NMR: ꢁ ¼ 7.35–7.24 (m, 5arom H), 6.14
(broad s, NH), 4.42 (d, J ¼ 5.6 Hz, benzyl–CH2), 3.98–3.80 (m, OCH2CH2O), 2.55 and 1.95 (2dd,
J ¼ 14.5, 4.8 and 14.5, 7.9 Hz, each 1H, CH2CON), 2.25–2.17 (m, CH), 1.85–1.75 and 1.68–1.58 (2m,
each 2H), 1.52–1.23 (m, 4H) ppm.
2-(1,4-Dioxaspiro[4.5]dec-6-yl)-N-methylacetamide (7b, C11H19NO3)
5a 4.53g (22.7 mmol), CDI 3.60 g (22.2mmol)=THF 70cm3. The solution was cooled to ꢃ20ꢁC and
added to a solution of 7 cm3 of methylamine in 30cm3 of THF at ꢃ40ꢁC under stirring. After removing
the cooling bath, the mixture was stirred for 1 h at ambient temperature, then for 8 h at 45ꢁC. Further
work up was accomplished following the general procedure. Yield 2.65g (55%) colourless crystals, mp
103ꢁC (Et2O); TLC (CH2Cl2:MeOH ¼ 10:0.8): Rf ¼ 0.47; IR (KBr): ꢂꢀ¼ 3260, 3089 (NH), 1636, 1574
(amide I=II) cmꢃ1; MS (EI): m=z (%) ¼ 213 (Mþꢄ, 9), 155 (28), 141 (12), 99 (100), 55 (28); 1H NMR:
ꢁ ¼ 5.92 (br s, NH), 4.01–3.87 (m, OCH2CH2O), 2.79 (m, NCH3), 2.52 and 1.91 (2dd, each J ¼ 14.4,
4.7 Hz, each 1H), 2.21–2.13 (m, 1H), 1.82–1.76 and 1.69–1.57 (2m, each 2H), 1.53–1.41 (m, 1H),
1.41–1.23 (m, 3H) ppm; 13C NMR: ꢁ ¼ 173.57 (C¼O), 110.17, 64.59, 64.55, 41.81, 36.52, 34.30,
30.16, 26.28, 24.54, 23.74 ppm.
2-(1,4-Dioxaspiro[4.5]dec-6-yl)-N-(1-phenylethyl)acetamide
(7c, C18H25NO3, diastereomeric mixture)
5a 4.89 g (24.5 mmol), CDI 3.88 g (24.0 mmol), (ꢅ)-1-phenylethylamine 3.85g (31.8 mmol), THF
100 cm3; yield 5.47 g (74%) colourless crystals, mp 110ꢁC (Et2O); TLC (CH2Cl2:MeOH¼ 10:0.2):
Rf ¼ 0.31=0.29; IR (KBr): ꢂꢀ¼ 3326 (NH), 1632, 1553 (amide I=II) cmꢃ1; MS (EI): m=z (%) ¼ 303
1
(Mþꢄ, 27), 258 (22), 155 (46), 120 (31), 105 (63), 99 (100); H NMR: ꢁ ¼ 7.36–7.29 (m, 4arom H),
7.27–7.22 (m, 1arom H), 6.10–6.08 (br m, NH), 5.13 (m, 1H), 3.99–3.77 (m, OCH2CH2O), 2.55–2.48,
2.22–2.13 and 1.95–1.88 (3m, each 1H), 1.81–1.72 and 1.67–1.54 (2m, each 2H), 1.49–1.16 (m, 4H),
1.47 (d, J ¼ 7.0 Hz, CH3) ppm; 13C NMR: ꢁ ¼ 171.79, 171.72, 143.49, 143.47, 128.54, 127.16, 126.17,
110.16, 110.12, 64.54, 64.53, 64.44, 64.39, 48.54, 48.51, 41.76, 41.68, 36.85, 36.23, 34.26, 30.63,
30.14, 24.49, 23.68, 21.81, 21.75 ppm.
2-(1,4-Dioxaspiro[4.5]dec-6-yl)-N-isopropylacetamide (7d, C13H23NO3)
5a 8.20 g (41.0mmol), CDI 6.51 g (40.2 mmol), isopropylamine 4.6 cm3 (53.8 mmol), THF 100 cm3;
yield 7.41g (75%) colourless crystals, mp 101ꢁC (Et2O); TLC (CH2Cl2:MeOH:NH3
(25%) ¼ 10:0.3:0.05): Rf ¼ 0.78; IR (KBr): ꢂꢀ¼ 3325 (NH), 1634, 1573 (amide I=II) cmꢃ1; MS (EI):
1
m=z (%) ¼ 241 (Mþꢄ, 3), 258 (22), 155 (38), 99 (100), 55 (45); H NMR: ꢁ ¼ 5.57 (br s, NH),

Angularly Substituted Perhydro N-Heterocycles by Bruylants Reaction
567
4.06–3.96 (m, J ¼ 6.7, 1.4, 1H), 3.95–3.81 (m, OCH2CH2O), 2.42 and 1.80 (2dd, J ¼ 14.3, 5.0 and
14.3, 8.3 Hz, each 1H), 2.14–2.06 (m, 1H), 1.76–1.68 and 1.62–1.52 (2m, each 2H), 1.47–1.18 (m,
4H), 1.08 (d, J ¼ 6.7 Hz, 2CH3) ppm; 13C NMR: ꢁ ¼ 171.69 (C¼O), 110.02, 64.46, 64.37, 41.64,
40.96, 36.66, 34.20, 29.88, 24.34, 23.59, 22.71, 22.66ppm.
N-Benzyl-3-(1,4-dioxaspiro[4.5]dec-6-yl)propionamide (7e, C18H25NO3)
5b 28.1g (132 mmol), CDI 20.9g (129 mmol), benzylamine 18.4g (172 mmol), THF 300 cm3; yield
28.84 g (72%) colourless crystals, mp 75ꢁC; TLC (CH2Cl2:MeOH¼ 10:0.2): Rf ¼ 0.46; IR (KBr):
ꢂꢀ¼ 3305 (NH), 1637 and 1538 (CONH) cmꢃ1; MS (EI): m=z (%) ¼ 303 (Mþꢄ, 25), 258 (26), 169
(11), 155 (27), 106 (32), 99 (100), 91 (63), 55 (49); 1H NMR: ꢁ ¼ 7.35–7.24 (m, 5arom H), 6.08 (broad
s, NH), 4.43 (d, J ¼ 5.7 Hz, benzyl–CH2), 3.95–3.84 (m, OCH2CH2O), 2.33 and 2.18 (2ddd, J ¼ 14.8,
9.0, 6.3 and 14.8, 8.8, 6.9 Hz, each 1H, CH2CON), 1.94 (dddd, J ¼ 13.6, 9.0, 6.9, 4.1 Hz, 1H, CH2–C–
CON), 1.78–1.71 (m, 2H), 1.66–1.53 (m, 3H), 1.51–1.39 (m, 2H), 1.35–1.15 (m, 3H) ppm; 13C NMR:
ꢁ ¼ 173.13, 138.60, 128.65 (2C), 127.88 (2C), 127.41, 110.78, 64.68, 64.45, 43.98, 43.58, 35.02, 34.46,
29.56, 24.68, 24.51, 23.72 ppm.
N-Benzyl-3-(1,4-dioxaspiro[4.4]non-6-yl)propionamide (8a, C17H23NO3)
6a 29.0g (145 mmol), CDI 23.0 g (142mmol), benzylamine 20.2g (189mmol), THF 330 cm3; yield
29.8g (71%) light yellow oil, bp 173–174ꢁC=3 Pa (the crude product contained some impurities,
which could not be removed by FC and attempted crystallization); TLC (CH2Cl2:MeOH¼ 10:0.2):
Rf ¼ 0.38; IR (film): ꢂꢀ¼ 3290 (NH), 1644 and 1546 (CONH) cmꢃ1; MS (EI): m=z (%) ¼ 289 (Mþꢄ, 9),
244 (21), 155 (9), 141 (20), 106 (27), 99 (100), 91 (52); 1H NMR: ꢁ ¼ 7.35–7.24 (m, 5arom H), 5.93
(broad s, NH), 4.44 (d, J ¼ 5.6 Hz, benzyl–CH2), 3.92–3.83 (m, OCH2–CH2O), 2.31–2.18 (m,
CH2CON), 1.98–1.82 and 1.76–1.72 (2m, each 3H), 1.71–1.54 (m, 2H), 1.38–1.30 (m, 1H) ppm.
N-Benzyl-2-(1,4-dioxaspiro[4.4]non-6-yl)acetamide (8b, C16H21NO3)
6b 14.18 g (76.2 mmol), CDI 12.09 g (74.7 mmol), benzylamine 10.61g (99.1mmol), THF 300 cm3;
yield 8.34g (40%) colourless crystals, mp 92ꢁC; TLC (CH2Cl2:MeOH¼ 10:0.2): Rf ¼ 0.54; IR (KBr):
ꢂꢀ¼ 3266 (NH), 1643 and 1561 (CONH) cmꢃ1; MS (EI): m=z (%) ¼ 275 (Mþꢄ, 10), 203 (30), 141 (27),
106 (27), 99 (100), 91 (74), 55 (32); 1H NMR: ꢁ ¼ 7.34–7.23 (m, 5arom H), 6.41 (broad s, NH), 4.44
and 4.38 (2dd, J ¼ 14.7, 5.8 and 14.7, 5.7Hz, each 1H, benzyl–CH2), 3.86–3.70 (m, OCH2CH2O),
2.50–2.41 (m, 2H), 2.24–2.13 and 2.02–1.93 (2m, each 1H), 1.81–1.72 and 1.72–1.57 (2m, each 2H),
1.45–1.32 (m, 1H) ppm; 13C NMR: ꢁ ¼ 172.38, 138.63, 128.63 (2C), 127.82 (2C), 127.38, 117.62,
64.60, 64.25, 43.58, 42.65, 36.65, 35.43, 30.02, 20.73ppm.
General Procedure for the Synthesis of Amines 9 and 10
To a solution of the amide 7 or 8 in anhydrous THF was added LiAlH4 during 20 min under stirring, ice
cooling, and N2. The mixture was allowed to warm up to ambient temperature, heated under reflux for
16h, diluted with 100 cm3 of Et2O, and then cautiously(!) poured into a mixture of 2 N NaOH and Et2O
(each 150 cm3) under stirring, cooling, and N2. After separating the organic layer the aqueous layer
was extracted with 3ꢂ150 cm3 of Et2O. The combined ether extracts were washed with 150 cm3 of
saturated Na2CO3 solution, dried (Na2SO4), and evaporated in vacuo. The crude products were used for
the next step without further purification, or, if necessary, were purified by FC (eluents are the same as
described under TLC).
Benzyl[2-(1,4-dioxaspiro[4.5]dec-6-yl)ethyl]amine (9a)
7a 12.47 g (43.1 mmol), LiAlH4 3.28 g (86.3 mmol), THF 250 cm3; yield 12.2 g (99%, Ref. [25] 88%)
colourless oil; TLC (CH2Cl2:MeOH:NH3 (25%) ¼ 10:0.2:0.1): Rf ¼ 0.23; IR (film): ꢂꢀ¼ 3313 (NH)

568
E. Reimann et al.
cmꢃ1; MS (EI): m=z (%) ¼ 275 (Mþꢄ, 2), 230 (33), 120 (66), 91 (100), 55 (19); 1H NMR data are in
line with those published in Ref. [25]; 13C NMR: ꢁ ¼ 139.56, 127.49 (2C), 127.29 (2C), 125.99,
109.79, 63.83, 63.65, 53.03, 46.81, 41.66, 33.70, 28.62, 27.86, 23.55, 22.82 ppm.
[2-(1,4-Dioxaspiro[4.5]dec-6-yl)ethyl]methylamine (9b, C11H21NO2)
7b 1.73g (8.1mmol), LiAlH4 616 mg (16.2mmol), THF 50cm3; yield 1.56g (97%) colourless oil;
TLC (CH2Cl2:MeOH:NH3 (25%) ¼ 10:0.5:0.1): Rf ¼ 0.30; IR (film): ꢂꢀ¼ 3312 (NH) cmꢃ1; MS: a.
(CI): m=z (%) ¼ 200 (Mþꢄþ1, 100), b. (EI): m=z (%) ¼ 199 (Mþꢄ, 5), 156 (91), 99 (75), 55 (100); 1H
NMR: ꢁ ¼ 3.99–3.90 (m, OCH2–CH2O), 2.63 and 2.54 (2ddd, J ¼ 11.3, 9.5, 5.3 and 11.3, 9.9, 6.8Hz,
each 1H, N–CH2), 2.43 (s, N–CH3), 1.73–1.67 and 1.67–1.59 (2m, each 3H), 1.53–1.42 (m, 1H),
1.40–1.20 (m, 4H) ppm; 13C NMR: ꢁ ¼ 110.74, 64.80, 64.65, 50.61, 42.80, 36.57, 34.69, 29.62, 28.78,
24.54, 23.84 ppm.
[2-(1,4-Dioxaspiro[4.5]dec-6-yl)ethyl](1-phenylethyl)amine (9c, C18H27NO2,
diastereomeric mixture)
7c 4.19g (13.8mmol), LiAlH4 1.05 g (27.6 mmol), THF 100 cm3; yield 3.67g (92%) colourless oil;
TLC (CH2Cl2:MeOH:NH3 (25%) ¼ 10:0.5:0.1): Rf ¼ 0.34; IR (film): ꢂꢀ¼ 3322 (NH) cmꢃ1; MS: a.
1
(CI): m=z (%) ¼ 290 (Mþꢄþ1, 100), b. (EI): m=z (%) ¼ 289 (Mþꢄ, 2), 274 (25), 105 (100); H NMR:
ꢁ ¼ 7.34–7.28 (m, 4arom H), 7.25–7.19 (m, 1arom H), 3.97–3.83 (m, OCH2CH2O), 3.75 (q,
J ¼ 6.5 Hz, 1H), 2.58–2.31 (m, 2H), 1.82–1.53 (m, 6H), 1.52–1.38 (m, 1H), 1.38–1.11 (m, 4H),
1.34 (d, J ¼ 6.5 Hz, CH3) ppm; 13C NMR: ꢁ ¼ 145.98, 128.35, 126.76, 126.74, 126.56, 110.70,
64.79, 64.75, 64.61, 64.58, 58.40, 46.13, 46.08, 42.80, 42.61, 34.77, 34.70, 29.68, 29.43, 29.32,
29.01, 24.56, 24.53, 24.47, 24.30, 23.81 ppm.
[2-(1,4-Dioxaspiro[4.5]dec-6-yl)ethyl]isopropylamine (9d, C13H25NO2)
7d 6.34 g (26.3 mmol), LiAlH4 2.00g (52.6mmol), THF 150 cm3; yield 5.43 g (91%) colourless oil;
TLC (CH2Cl2:MeOH:NH3 (25%) ¼ 10:0.3:0.05): Rf ¼ 0.59; IR (film): ꢂꢀ¼ 3157 (NH) cmꢃ1; MS:
a. (CI): m=z (%) ¼ 228 (Mþꢄþ1, 100), b. (EI): m=z (%) ¼ 227 (Mþꢄ, 1), 212 (11), 184 (14), 125
1
(15), 99 (16), 72 (100), 55 (29); H NMR: ꢁ ¼ 3.99–3.91 (m, OCH2CH2O), 2.79 (sept, J ¼ 6.2 Hz,
N–CH), 2.66 (dt, J ¼ 10.9, 5.4Hz, 1H), 1.82–1.73 and 1.67–1.57 (2m, each 3H), 1.54–1.42 (m, 1H),
1.39–1.17 (m, 4H), 1.05 and 1.04 (2d, each J ¼ 6.2 Hz, 2CH3) ppm; 13C NMR: ꢁ ¼ 110.61, 64.70,
64.52, 48.64, 45.98, 42.80, 34.58, 29.51, 29.16, 24.41, 23.66, 22.91, 22.82 ppm.
Benzyl[3-(1,4-dioxaspiro[4.5]dec-6-yl)propyl]amine (9e, C18H27NO2)
7e 9.97 g (32.9 mmol), LiAlH4 2.49 g (66.0 mmol), THF 200 cm3; yield 9.3 g (98%) colourless oil;
TLC (CH2Cl2:MeOH ¼ 10:0.3): Rf ¼ 0.21; IR (film): ꢂꢀ¼ 3313 (NH) cmꢃ1; MS: a. (CI): m=z (%) ¼ 290
(Mþꢄþ1, 100), b. (EI): m=z (%) ¼ 244 (62), 120 (48), 99 (11), 91 (100), 55 (16); 1H NMR: ꢁ ¼ 7.32–
7.30 (m, 4arom H), 7.27–7.21 (m, 1arom H), 3.98–3.87 (m, OCH2CH2O), 3.78 (s, benzyl–CH2), 2.67–
2.56 and 1.84–1.71 (2m, each 2H), 1.67–1.38 (m, 8H), 1.38–1.27 (m, 1H), 1.27–1.16 (m, 2H),
1.15–1.07 (m, 1H) ppm; 13C NMR: ꢁ ¼ 140.61, 128.35 (2C), 128.12 (2C), 126.84, 110.87, 64.74,
64.63, 54.06, 49.83, 44.50, 34.61, 29.08, 28.05, 25.74, 24.48, 23.89 ppm.
2-(1,4-Dioxaspiro[4.5]dec-6-yl)ethylamine (9f)
19a [28] 5.04 g (27.8 mmol), LiAlH4 2.00 g (52.6 mmol), THF 100 cm3; refluxing time 4 h; yield
4.73g (92%, Ref. [28] 78%) colourless oil; TLC (CH2Cl2:MeOH:NH3 (25%) ¼ 10:0.8:0.1):
Rf ¼ 0.28; IR (film): ꢂꢀ¼ 3364 (NH) cmꢃ1; MS (CI): m=z (%) ¼ 186 (Mþꢄþ1, 100); 169 (25);

Angularly Substituted Perhydro N-Heterocycles by Bruylants Reaction
569
1H NMR: ꢁ ¼ 4.05–3.89 (m, OCH2CH2O), 2.77 and 2.64 (2ddd, J ¼ 15.0, 9.3, 5.3 and 15.0, 8.6,
6.9 Hz, each 1H, N–CH2), 1.79–1.51 (m, 6H), 1.30–1.11 (m, 7H) ppm.
3-(1,4-Dioxaspiro[4.5]dec-6-yl)propylamine (9g)
19b [13] 13.5g (69.2 mmol), LiAlH4 4.00 g (105.3mmol), THF 250 cm3; refluxing time 4 h; yield
13.6g (99%, Ref. [13] 74%) colourless oil; TLC (CH2Cl2:MeOH:NH3 (25%) ¼ 10:0.5:0.1): Rf ¼ 0.21;
1
IR (film): ꢂꢀ¼ 3370 (NH) cmꢃ1; MS (CI): m=z (%) ¼ 200 (Mþꢄþ1, 100); 199 (Mþꢄ, 58); H NMR:
ꢁ ¼ 4.00–3.88 (m, OCH2–CH2O), 2.71–2.63 and 1.88–1.70 (2m, each 2H), 1.67–1.41 (m, 9H), 1.40–
1.16 (m, 3H), 1.15–1.04 (m, 1H) ppm; 13C NMR: ꢁ ¼ 110.87, 64.76, 64.65, 44.47, 42.55, 34.61, 31.83,
29.10, 25.27, 24.51, 23.87 ppm.
Benzyl[3-(1,4-dioxaspiro[4.4]non-6-yl)propyl]amine (10a, C17H25NO2)
8a 15.05 g (52.1 mmol), LiAlH4 3.96 g (104.2mmol), THF 250 cm3; yield 13.5 g (94%) colourless oil;
TLC (CH2Cl2:MeOH ¼ 10:0.4): Rf ¼ 0.18; IR (film): ꢂꢀ¼ 3313 (NH) cmꢃ1; MS: a. (CI): m=z (%) ¼ 276
(Mþꢄþ1,100),b. (EI):m=z(%) ¼ 230(59),120(43),106(6),91(100);1HNMR:ꢁ ¼ 7.34–7.29(m, 4arom
H), 7.27–7.21 (m, 1arom H), 3.94–3.82 (m, OCH2CH2O), 3.79 (s, 2H), 2.69–2.58 (m, 2H), 2.10 (br s,
NH), 1.95–1.83(m, 2H),1.79–1.43(m, 7H),1.37–1.16(m, 2H)ppm;13CNMR:ꢁ ¼ 140.55, 128.33 (2C),
128.10 (2C), 126.81, 118.17, 64.55, 64.40, 54.09, 49.80, 46.06, 35.69, 29.46, 28.80, 26.64, 20.63 ppm.
Benzyl[2-(1,4-dioxaspiro[4.4]non-6-yl)ethyl]amine (10b, C16H23NO2)
8b 6.11 g (22.2 mmol), LiAlH4 1.69g (44.8mmol), THF 120 cm3; yield 5.79 g (98%) colourless oil;
TLC (CH2Cl2:MeOH:NH3 (25%) ¼ 10:0.3:0.1): Rf ¼ 0.35; IR (film): ꢂꢀ¼ 3313 (NH) cmꢃ1; MS (EI):
1
m=z (%) ¼ 262 (Mþꢄþ1, 2), 216 (21), 120 (57), 99 (15), 91 (100), 55 (16); H NMR: ꢁ ¼ 7.30 (m,
4arom H), 7.26–7.20 (m, 1arom H), 3.92–3.81 (m, OCH2CH2O), 3.80 and 3.77 (2d, each J ¼ 13.1Hz,
each 1H, N-benzyl–CH2), 2.68 and 2.61 (2ddd, J ¼ 11.3, 9.2, 3.6 and 11.3, 9.00, 6.4Hz, each 1H),
2.00–1.91 (m, 1H), 1.87 (ddt, J ¼ 12.1, 7.9, 3.7 Hz, 1H), 1.78–1.55 (m, 5H), 1.45 (ddt, J ¼ 13.1, 9.0,
5.6 Hz, 1H), 1.42–1.28 (m, 2H) ppm; 13C NMR: ꢁ ¼ 140.66, 128.33 (2C), 128.09 (2C), 126.80, 118.20,
64.54, 64.45, 54.04, 48.22, 44.11, 35.69, 29.65, 29.46, 20.71 ppm.
General Procedure for the Synthesis of Bicyclic ꢀ-Aminonitriles 11–14
The amine 9 or 10 was dissolved in 2 N HCl and H2O, if necessary under warming up to 40–50ꢁC. After
the mixturewas stirredfor 1.5 h at ambient temperature, an aqueous solutionofKCN was dropwise added
over a period of 20min under vigorous stirring. Thereafter the reaction mixture exhibited a pH of 7–8;
deviations of this value were corrected by addition of a small amount of 2N HCl or KCN. Stirring of the
mixturewas continued for 1 h. The oily product separated was dissolved in 100cm3 of Et2O. The aqueous
layer was rendered alkaline by saturated Na2CO3 solution and extracted with 3ꢂ100 cm3 of Et2O. The
combined organic layers were washed with 200 cm3 of brine, dried (Na2SO4), and evaporated in vacuo.
The crude products were used for the next step without further purification. Attempted purification by FC
caused decomposition and remarkable loss of the products.
cis=trans-1-Benzyloctahydroindole-7a-carbonitrile (11a, C16H20N2,
diastereomeric mixture)
9a 10.31 g (37.5 mmol), 2 N HCl 37.5cm3 (75.0mmol), H2O 300 cm3, KCN 4.88g (75.0 mmol)=H2O
10cm3; yield 8.84g (98%) light yellow oil; TLC (Al2O3, n-hexane:Et2O ¼ 8:2): Rf ¼ 0.58; IR (film):
ꢂꢀ¼ 2214 (CN) cmꢃ1; MS (EI): m=z (%) ¼ 240 (Mþꢄ, 11), 213 (32), 184 (23), 149 (16), 91 (100);
1H NMR: ꢁ ¼ 7.35–7.22 (m, 5arom H), 4.03 and 3.42 (2d, each J ¼ 12.8Hz, each 0.3H), 4.00 and 3.36

570
E. Reimann et al.
(2d, each J ¼ 13.3 Hz, each 0.7H), 3.08–2.99 and 2.46–2.38 (2m, each 1H), 2.34–2.28 (m, 0.7H),
2.23–2.09 (m, 1.7H), 1.91–1.76 (m, 2.2H), 1.74–1.55 (m, 2H), 1.55–1.36 (m, 3.4H), 1.36–1.21 (m,
1H) ppm; 13C NMR: ꢁ ¼ 138.83, 137.67, 127.75, 127.48, 127.43, 127.41, 126.26, 126.17, 119.64,
117.23, 68.07, 63.53, 53.81, 53.14, 49.23, 48.73, 47.30, 42.42, 32.92, 29.14, 27.72, 26.60, 26.35, 25.37,
24.24, 23.42, 21.42, 18.54 ppm.
cis=trans-1-Methyloctahydroindole-7a-carbonitrile (11b, C10H16N2,
diastereomeric mixture)
9b 1.39g (7.0mmol), 2 N HCl 7.0cm3 (14.0mmol), H2O 50 cm3, KCN 910 mg (14.0 mmol)=H2O 5 cm3;
yield 1.06 g (92%) light yellow oil; IR (film): ꢂꢀ¼ 2214 (CN) cmꢃ1; MS (EI): m=z (%) ¼ 137 (Mþꢄ
–
HCN, 71), 109 (100); 1H NMR: ꢁ ¼ 3.22–3.15 (m, 0.33H), 3.18 (dt, J ¼ 9.5, 5.3 Hz, 0.66H), 2.52 and
2.45 (2ddd, J ¼ 11.0, 9.5, 5.1 and 10.8, 10.0, 4.1 Hz, 0.66 and 0.33H), 2.37 and 2.31 (2s, 1 and 2H, N–
CH3), 2.30–2.22 (m, 0.66H), 2.21–2.01 (m, 1.66H), 1.97–1.80 (m, 1.33H), 1.80–1.53 and 1.53–1.31
(2m, each 3H), 1.31–1.18 (m, 1.33H) ppm; 13C NMR: ꢁ ¼ 120.00, 117.44, 69.61, 65.25, 52.05, 52.91,
48.39, 43.23, 35.81, 35.38, 33.23, 29.64, 29.00, 27.60, 27.43, 26.43, 25.10, 24.26, 22.36, 19.31 ppm.
1-(1-Phenylethyl)octahydroindole-7a-carbonitrile (11c, C17H22N2,
mixture of 4 diastereomers)
9c 3.53 g (12.2 mmol), 2 N HCl 12.2cm3 (24.4 mmol), H2O 100 cm3, KCN 1.59g (24.4 mmol)=H2O
10cm3; yield 3.01 g (97%) pale yellow oil; TLC (n-hexane:Et2O ¼ 8:2): Rf ¼ 0.59; IR (film): ꢂꢀ¼ 2214
(CN) cmꢃ1; MS: a. (CI): m=z (%) ¼ 228 (Mþꢄþ1–HCN, 100), 124 (13), 105 (11), b. (EI): m=z
1
(%) ¼ 227 (Mþꢄ –HCN, 11), 105 (100); H NMR: ꢁ ¼ 7.38–7.19 (m, 5arom H), 4.02 and 3.93 (2q,
J ¼ 6.8 Hz, 0.38 and 0.13H), 3.82–3.74 (m, 0.5H), 3.33 (ddd, J ¼ 9.9, 9.1, 6.0 Hz, 0.38H), 3.00–2.93
(m, 0.5H), 2.88 (m, 0.38H), 2.83–2.80 (m, 0.13H), 2.75–2.63 (m, 0.5H), 2.57–2.50 (m, 0.13H), 2.38–
2.23 (m, 0.75H), 2.12–2.02 (m, 0.38H), 2.00–1.20 (m, 8.75H), 1.51, 1.46, 1.44, and 1.42 (4d, each
J ¼ 6.8 Hz, 1.13, 0.38, 0.38, and 1.13H, CH3), 1.08 (tq, J ¼ 13.3, 4.3 Hz, 0.38H), 0.93 and 0.83 (2dt,
J ¼ 12.9, 3.5 and 12.9, 4.0 Hz, each 0.38H) ppm.
cis=trans-1-Isopropyloctahydroindole-7a-carbonitrile (11d, C12H20N2,
diastereomeric mixture)
9d 1.48 g (6.52 mmol), 2 N HCl 6.5cm3 (13.0 mmol), H2O 80cm3, KCN 845 mg (13.0mmol)=H2O
5 cm3; yield 1.2 g (96%) light yellow oil; IR (film): ꢂꢀ¼ 2212 (CN) cmꢃ1; MS (EI): m=z (%) ¼ 165
1
(Mþꢄ –HCN, 55), 150 (100), 122 (65); H NMR: ꢁ ¼ 3.18–3.07 (m, 0.33H), 3.17 and 3.08 (2sept,
J ¼ 6.7 and 6.5Hz, 0.66 and 0.33H, N–CH), 3.02–2.90 (m, 1.33H), 2.73 (ddd, J ¼ 10.9, 9.7, 3.2Hz,
0.33H), 2.35 (dt, J ¼ 12.5, 3.2Hz, 0.33H), 2.27–2.20, 2.13–2.01, and 1.93–1.67 (3m, 0.66, 1.33, and
2.33H) ppm; 13C NMR: ꢁ ¼ 123.81, 119.72, 66.76, 61.55, 49.67, 49.27, 45.88, 45.55, 44.23, 41.32,
35.64, 30.11, 27.71, 27.21, 27.17, 26.41, 25.15, 23.72, 23.56, 23.09, 22.49, 19.61, 19.26, 16.25 ppm.
trans-1-Benzyloctahydroquinoline-8a-carbonitrile (12a, C17H22N2)
9e 10.23 g (35.4 mmol), 2 N HCl 35.4 cm3 (70.8mmol), H2O 300 cm3, KCN 4.60 g (70.8 mmol)=H2O
10cm3; yield 8.86g (99%) light yellow oil; TLC (Al2O3, n-hexane:Et2O ¼ 8:2): Rf ¼ 0.60; IR (film):
ꢂꢀ¼ 2215 (CN) cmꢃ1; MS (EI): m=z (%) ¼ 254 (Mþꢄ, 3), 227 (100), 226 (61), 198 (36), 136 (10), 91
(90); 1H NMR: ꢁ ¼ 7.34–7.28 (m, 4arom H), 7.27–7.21 (m, 1H), 4.18 and 3.11 (2d, each J ¼ 13.9Hz,
each 1H, benzyl–CH2), 2.80–2.74 (m, among others J ¼ 12.2Hz, 1H), 2.40 (br dt, J ¼ 13.1, 3.0Hz,
1H), 2.34 (dt, J ¼ 12.2, 3.2 Hz, 1H), 1.88–1.81, 1.79–1.72, and 1.74–1.63 (3m, each 1H), 1.63–1.34
(m, 8H), 1.36–1.22 (m, 1H) ppm; 13C NMR: ꢁ ¼ 139.43, 128.42 (2C), 128.39 (2C), 126.92, 117.97,
65.98, 54.73, 50.08, 44.94, 34.82, 30.38, 29.23, 25.28, 25.11, 23.52 ppm.

Angularly Substituted Perhydro N-Heterocycles by Bruylants Reaction
trans-Octahydroquinoline-8a-carbonitrile (12b, C10H16N2)
571
22 2.80g (14.1 mmol), 2 N HCl 14.0cm3 (28.0mmol), H2O 300 cm3, KCN 1.83mg (28.2 mmol)=H2O
20cm3. After stirring for 1 h the reaction mixture was decanted from lumpy precipitate possibly
separated and rendered alkaline with Na2CO3. Further workup was accomplished following the general
procedure. Yield 1.69 g (73%) light yellow oil; IR (film): ꢂꢀ¼ 3322 (NH), 2216 (CN) cmꢃ1; MS (EI):
m=z (%) ¼ 137 (Mþꢄ –HCN, 100); 1H NMR: ꢁ ¼ 3.10–2.97 and 1.94–1.87 (2m, 2 and 1H), 1.83–1.66
(m, 5H), 1.64–1.48 and 1.45–1.25 (2m, each 4H) ppm; 13C NMR: ꢁ ¼ 120.81, 61.18, 44.35, 43.65,
37.39, 29.75, 28.83, 25.53, 25.45, 23.00 ppm.
cis=trans-1-Benzyloctahydro-1-pyrindine-7a-carbonitrile
(13, C16H20N2, diastereomeric mixture)
10a 9.40g (34.2 mmol), 2 N HCl 34.2cm3 (68.4mmol), H2O 400 cm3, KCN 4.45g (68.4 mmol)=H2O
10cm3; yield 8.02 g (98%) light yellow oil, which crystallized during several hours, mp 77ꢁC (after
washing with a small volume of ice cold Et2O); TLC (Al2O3, n-hexane:Et2O ¼ 8:1): Rf ¼ 0.52; IR
(film): ꢂꢀ¼ 2217 (CN) cmꢃ1; MS (EI): m=z (%) ¼ 239 (Mþꢄ –1, 5), 213 (20), 212 (26), 91 (100);
1H NMR: ꢁ ¼ 7.35–7.22 (m, 5arom H), 4.00 and 3.16 (2d, each J ¼ 14.4Hz, each 0.66H), 3.95 and
3.30 (2d, each J ¼ 13.3Hz, each 0.33H), 2.76–2.72 (m, 0.33H), 2.71–2.66 (m, 0.66H), 2.40–2.37 (m,
1.66H), 2.25–2.16 (m, 1H), 2.04–1.93 (m, 2H), 1.74–1.63 (m, 6H), 1.48–1.37 (m, 1.33H) ppm;
13C NMR: ꢁ ¼ 139.05, 138.36, 18.70, 128.36, 128.30, 128.13, 127.14, 126.98, 119.52, 118.44,
70.38, 64.56, 58.02, 56.18, 49.18, 48.94, 48.84, 45.64, 37.16, 36.14, 27.42, 26.36, 26.26, 25.32,
22.99, 21.78, 20.41, 19.07 ppm.
cis-1-Benzylhexahydrocyclopenta[b]pyrrole-6a-carbonitrile (14, C15H18N2)
10b 4.23 g (26.3 mmol), 2 N HCl 26.3cm3 (52.6mmol), H2O 220cm3, KCN 3.42g (52.6 mmol)=H2O
10cm3; yield 5.71g (98%) light yellow oil; TLC (Al2O3, n-hexane:Et2O ¼ 8:1): Rf ¼ 0.46; IR (film):
ꢂꢀ¼ 2217 (CN) cmꢃ1; MS (EI): m=z (%) ¼ 226 (Mþꢄ, 12), 225 (Mþꢄ–1, 23), 91 (100), 84 (23), 57 (27);
1H NMR: ꢁ ¼ 7.33–7.30 (m, 4arom H), 7.29–7.23 (m, 1arom H), 3.95 and 3.54 (2d, each J ¼ 13.4Hz,
each 1H, N-benzyl–CH2), 3.03–2.92 (m, 1H), 2.87 (m, 1H), 2.36 (ddd, J ¼ 11.0, 9.6, 6.1 Hz, 1H), 2.08
(br ddd, J ¼ 12.3, 9.6, 5.9 Hz, 1H), 2.05–1.98 (m, 1H), 1.94–1.80 and 1.80–1.69 (2m, each 2H), 1.59–
1.50 (m, 1H), 1.38 (ddt, J ¼ 12.3, 11.0, 7.3 Hz, 1H) ppm; 13C NMR: ꢁ ¼ 138.80, 128.44 (2C), 128.33
(2C), 127.14, 120.73, 69.68, 55.04, 52.51, 50.94, 37.70, 33.72, 31.15, 24.86 ppm.
Angularly Substituted Compounds 15–18
A. General Procedure for the Synthesis of 7a-Methyl- and 7a-Aryl-derivatives
15a–15f, 15i, 15k, 16b, 16c, 17b, and 18
The Grignard reagent was prepared from Mg and the corresponding halogenide in anhydrous THF and
the reaction was completed by heating the mixture to reflux (temperature of the oil bath 70ꢁC). A
solution of the aminonitrile 11–14 in toluene was slowly added over a period of 45min under vigorous
stirring and N2. After the addition was complete the temperature of the heating bath was raised to
130ꢁC and the mixture was stirred for additional 16h, then quenched with 50cm3 of saturated NH4Cl
solution under ice cooling and diluted with 300cm3 of Et2O and 200 cm3 of 1 N HCl. The aqueous
layer was separated and the organic phase was extracted with 3ꢂ100 cm3 of 0.5 N HCl. The combined
aqueous layers were rendered alkaline with saturated Na2CO3 solution and extracted with 3ꢂ200 cm3
of Et2O. After drying the ether extracts with Na2SO4 and removing the solvent in vacuo the crude
product was purified by FC (neutral Al2O3; for eluent see TLC).

572
E. Reimann et al.
cis-1-Benzyl-7a-phenyloctahydroindole (15a, C21H25N)
Mg 1.20g (50.0 mmol)=THF 5 cm3, bromobenzene 7.85 g (50.0mmol)=THF 30 cm3, 11a 3.0 g
(12.5mmol)=toluene 50 cm3; yield 909 mg (25%) colorless crystals, mp 73ꢁC (MeOH); TLC
(Al2O3, n-hexane:Et2O ¼ 8:1): Rf ¼ 0.78; MS (EI): m=z (%) ¼ 291 (Mþꢄ, 36), 248 (100), 214 (15),
91 (77); 1H NMR: ꢁ ¼ 7.70–7.67 (dd, J ¼ 8.5, 1.2Hz, 2arom H), 7.37–7.32 (m, 2arom H), 7.25–7.13
(m, 6arom H), 3.45 and 3.14 (2d, each J ¼ 13.0Hz, each 1H, benzyl–CH2), 3.02 (dt, J ¼ 9.1, 5.2 Hz,
1H), 2.57–2.48 (m, 2H), 2.14–2.08 (m, 1H), 1.95–1.78 (m, 3H), 1.65 (m, 1H), 1.63–1.41 (m, 4H),
1.35–1.25 (m, 1H) ppm; 13C NMR: ꢁ ¼ 145.61, 140.99, 128.42 (2C), 128.39 (2C), 128.11 (2C), 127.87
(2C), 126.52, 126.49, 66.49, 52.67, 48.87, 46.67, 25.93, 23.50, 23.74, 22.87, 20.26 ppm.
Table 1. Crystallographic data of 15aa
Formula
C21H25N
291.44
Formula weight
Temperature=K
Color, shape
294
Colourless rods
0.27ꢂ0.33ꢂ0.47
triclinic
Crystal dimensions=mm
Crystal system
Space group
P1
Cell dimensions:
˚
a=A
7.847(2)
˚
b=A
9.7580(10)
11.646(4)
73.73(2)
˚
c=A
ꢀ=ꢁ
ꢃ=ꢁ
ꢄ=ꢁ
83.28(2)
77.147(13)
833.2(3)
3
˚
V=A
˚
Radiaton
MoKꢀ (ꢅ ¼ 0.71073 A)
ꢁ
ꢁ
min–ꢁmax
=
2.48–23.97
Z
2
F(000)
m=mmꢃ1
Density=g cmꢃ3
316
0.066
1.167
Reflections collected
Independent reflections
Observed reflections
No. of parameters refined
R-values
5656
2601 (Ri ¼ 0.0341)
2107 (I > 2ꢆ(I))
199=0
R1 (2ꢆ(I)=all data)
wR2 (2ꢆ(I)=all data)
Goodness of Fit
˚
Residual electron density (e=A )
System used
0.0414=0.0528
0.1054=0.1143
1.111
3
0.141=ꢃ0.144
SHELXS-86=SHELXL-93 [29]
a
Further details of the crystal structure determination are available from Cambridge Crystallographic
Data Center, 12 Union Road, GB Cambridge CB21EZ quoting the deposition number CCDC 169365
and the complete literature source (E-mail: deposit@ccdc.cam.ac.uk)

Angularly Substituted Perhydro N-Heterocycles by Bruylants Reaction
cis-1-Benzyl-7a-(3-methoxyphenyl)octahydroindole (15b, C22H27NO)
573
Mg 2.78 g (116.0 mmol)=THF 10 cm3, 3-bromoanisol 21.69 g (116.0mmol)=THF 70cm3, 11a 6.96g
(29.0mmol)=toluene 50cm3; yield 1.56g (17%) colourless oil; TLC (Al2O3, n-hexane:Et2O ¼ 9:1):
Rf ¼ 0.51; MS (EI): m=z (%) ¼ 321 (Mþꢄ, 38), 278 (100), 214 (17); 1H NMR: ꢁ ¼ 7.28–7.15 (m, 8arom
H), 6.79–6.73 (m, 1arom H), 3.83 (s, OCH3), 3.48 and 3.15 (2d, each J ¼ 13.1Hz, each 1H, benzyl–
CH2), 3.02 (dt, J ¼ 9.2, 5.1Hz, 1H), 2.55–2.47 (m, 2H), 2.10–2.05 (m, 1H), 1.95–1.78 (m, 3H), 1.72–
1.56 (m, 2H), 1.56–1.43 (m, 3H), 1.37–1.25 (m, 1H) ppm; 13C NMR: ꢁ ¼ 159.48, 147.71, 140.99,
128.61, 128.38 (2C), 128.10 (2C), 126.50, 120.93, 114.52, 111.55, 66.53, 55.24, 52.64, 48.80, 46.69,
25.91, 25.50, 23.75, 23.08, 20.27 ppm.
cis-1-Benzyl-7a-(4-methoxyphenyl)octahydroindole (15c, C22H27NO)
Mg 0.53g (21.8 mmol)=THF 5 cm3, 4-bromoanisol 4.10 g (21.8 mmol)=THF 20cm3, 11a 1.31g
(5.45 mmol)=toluene 20 cm3; yield 1.56g (17%) colorless oil; TLC (Al2O3, n-hexane:Et2O ¼ 9:1):
1
Rf ¼ 0.51; MS (EI): m=z (%) ¼ 321 (Mþꢄ, 29), 278 (100), 214 (7); H NMR: ꢁ ¼ 7.59 (m, 2arom
H), 7.25–7.13 (m, 5arom H), 6.89 (br t, J ¼ 9.0 Hz, 2arom H), 3.81 (s, OCH3), 3.45 and 3.10 (2d, each
J ¼ 13.0Hz, each 1H, benzyl–CH2), 3.00 (dt, J ¼ 9.3, 5.4 Hz, 1H), 2.54–2.45 (m, 2H), 2.09–2.03 (m,
1H), 1.93–1.77 (m, 3H), 1.67–1.42 (m, 5H), 1.35–1.25 (m, 1H) ppm; 13C NMR: ꢁ ¼ 158.17, 141.06,
137.29, 129.48 (2C), 128.43 (2C), 128.11 (2C), 126.49, 113.15 (2C), 66.06, 55.23, 52.58, 48.74, 46.41,
25.74, 25.42, 23.76, 22.74, 20.27 ppm.
cis-1-Benzyl-7a-(3,4-dimethoxyphenyl)octahydroindole (15d, C23H29NO2)
Mg 2.88 g (120.0mmol)=THF 10 cm3, 4-bromo-1,2-dimethoxybenzene 25.04g (120.0mmol)=THF
80cm3, 11a 7.23 g (30.0 mmol)=toluene 50 cm3; yield 1.26g (12%) colourless oil; TLC (Al2O3, n-
1
hexane:Et2O ¼ 7:3): Rf ¼ 0.38; MS (EI): m=z (%) ¼ 351 (Mþꢄ, 25), 308 (100), 214 (11), 91 (65); H
NMR: ꢁ ¼ 7.33 (d, J ¼ 2.1 Hz, 1arom H), 7.25–7.15 (m, 5arom H), 7.14 (dd, J ¼ 8.4, 2.1Hz, 1arom H),
6.82 (d, J ¼ 8.4 Hz, 1arom H), 3.93 and 3.88 (2s, 2OCH3), 3.47 and 3.10 (2d, each J ¼ 13.1 Hz, each
1H, benzyl–CH2), 3.04 (dt, J ¼ 8.9, 5.2 Hz, 1H), 2.53–2.43 (m, 2H), 2.09–2.03 (m, 1H), 1.93–1.80 (m,
3H), 1.68–1.44 (m, 5H), 1.37–1.25 (m, 1H) ppm; 13C NMR: ꢁ ¼ 148.64, 147.63, 140.82, 138.07,
128.24 (2C), 127.94 (2C), 126.36, 120.61, 111.65, 109.85, 66.29, 55.93, 55.77, 52.50, 48.65, 46.57,
25.71, 25.39, 23.86, 22.93, 20.17 ppm.
cis-1-Benzyl-7a-(3,4-methylenedioxyphenyl)octahydroindole (15e, C22H25NO2)
Mg 2.88g (120.0mmol)=THF 10 cm3, 4-bromo-1,2-methylenedioxybenzene 24.87 g (120.0mmol)=
THF 80 cm3, 11a 7.23 g (30.0mmol)=toluene 50 cm3; yield 1.43g (14%) colourless crystals, mp 96ꢁC
(MeOH); TLC (Al2O3, n-hexane:Et2O ¼ 9:1): Rf ¼ 0.49; MS (EI): m=z (%) ¼ 335 (Mþꢄ, 30), 292
1
(100), 214 (10), 91 (80); H NMR: ꢁ ¼ 7.26–7.14 (m, 6arom H), 7.09 (dd, J ¼ 8.3, 2.0 Hz, 1arom
H), 6.76 (d, J ¼ 8.3Hz, 1H), 5.95 and 5.94 (2d, each J ¼ 2.0Hz, each 1H, OCH2O), 3.47 and 3.11 (2d,
each J ¼ 13.4Hz, each 1H, benzyl–CH2), 3.00 (dt, J ¼ 9.3, 5.2 Hz, 1H), 2.50–2.41 (m, 2H), 2.05–1.98
(m, 1H), 1.93–1.77 (m, 3H), 1.66–1.42 (m, 5H), 1.36–1.25 (m, 1H) ppm; 13C NMR: ꢁ ¼ 147.57,
145.96, 140.78, 139.55, 128.28 (2C), 128.02 (2C), 126.42, 121.50, 108.81, 107.08, 100.80, 66.39,
52.47, 48.66, 46.61, 25.67, 25.36, 23.70, 23.09, 20.16ppm.
cis-1-Methyl-7a-phenyloctahydroindole (15f)
Mg 339 mg (16.4 mmol)=THF 3 cm3, bromobenzene 2.61 g (16.6 mmol)=THF 10cm3, 11b 682 mg
(4.16 mmol)=toluene 20 cm3; yield 306 mg (34%) colorless powder, mp 189ꢁC (Ref. [5] oil, bp 115–
120ꢁC=15.6Pa); TLC (Al2O3, n-hexane:Et2O ¼ 10:1): Rf ¼ 0.66; MS (EI): m=z (%) ¼ 215 (Mþꢄ, 22),

574
E. Reimann et al.
1
172 (100), 138 (20); H NMR: ꢁ ¼ 7.55–7.52 and 7.35–7.31 (2m, each 2arom H), 7.22 (tt, J ¼ 7.2,
1.5 Hz, 1arom H), 3.21 (dt, J ¼ 9.5, 4.4 Hz, 1H), 2.68–2.57 and 2.10–1.94 (2m, each 2H), 1.98 (s, N–
CH3), 1.90–1.80 and 1.77–1.71 (2m, each 1H), 1.55–1.25 (m, 6H) ppm; 13C NMR: ꢁ ¼ 127.90 (2C),
127.87 (2C), 126.42, 51.66, 45.58, 33.90, 25.88, 25.46, 23.28, 21.63, 20.44ppm.
cis-(1RS)-7a-Methyl-1-(1-phenylethyl)octahydroindole
(15i, C17H25N, diastereomeric mixture)
Preparation according to 15k: 11c 330 mg (1.3mmol)=THF 5 cm3, 3 M CH3MgBr in Et2O 2 cm3
(6mmol). The mixture was separated by FC (silica gel, EtOAc:MeOH:NH3 (25%) ¼ 10:0.7:0.2) giving
the diastereomers cis-A and cis-B.
Diastereomer cis-A. Yield 120 mg (38%) colourless oil; TLC (EtOAc:MeOH:NH3 (25%) ¼
1
10:0.2:0.1): Rf ¼ 0.56; MS (CI): m=z (%) ¼ 244 (Mþꢄþ1, 100); H NMR: ꢁ ¼ 7.35 (br d, J ¼ 7.2 Hz,
2arom H), 7.27 (br t, J ¼ 7.2Hz, 2arom H), 7.17 (tt, J ¼ 7.2, 1.6 Hz, 1arom H), 3.92 (q, J ¼ 6.9 Hz, N–
CH), 2.84 and 2.69 (2dt, J ¼ 9.5, 4.6 and 9.5, 5.4Hz, each 1H), 1.85 and 1.68 (2m, 2 and 6H), 1.39 (d,
J ¼ 6.9 Hz, CH3–C–Ph), 1.31–1.20 and 1.20–1.12 (each m, 2 and 1H), 1.15 (s, CH3) ppm; 13C NMR:
ꢁ ¼ 146.69, 127.99 (2C), 127.52 (2C), 126.21, 61.52, 55.67, 45.12, 45.06, 31.11, 27.83, 26.46, 24.59,
23.04, 22.19, 21.38 ppm.
Diastereomer cis-B. Yield 98 mg (31%) colourless oil; TLC: Rf ¼ 0.27; MS (EI): m=z (%) ¼ 243
1
(Mþꢄ, 8), 105 (43), 57 (100); H NMR: ꢁ ¼ 7.37 (br d, J ¼ 7.2 Hz, 2arom H), 7.27 (br t, J ¼ 7.2 Hz,
2arom H), 7.21–7.16 (m, 1arom H), 3.88 (q, J ¼ 6.7 Hz, N–CH), 3.00–2.91 and 2.83–2.76 (2m,
each 1H), 1.85–1.71, 1.64–1.48, and 1.43–1.30 (3m, 2, 5 and 3H), 1.39 (d, J ¼ 6.7 Hz, CH3–C-Ph),
1.22–1.11 (m, 1H), 0.77 (s, CH3) ppm; 13C NMR: ꢁ ¼ 147.32, 127.91 (2C), 127.49 (2C), 126.25,
61.45, 55.77, 45.35, 44.48, 29.22, 26.12, 25.02, 24.28, 22.60, 21.63, 21.45 ppm.
cis-1-Benzyl-7a-methyloctahydroindole (15k)
To a solution of 230 mg (0.96 mmol) of 11a in 5 cm3 of anhydrous THF was added 2 cm3 (6mmol) of
3 M CH3MgBr (Et2O) under N2 and stirring. After stirring 8 h at ambient temperature the reaction was
quenched under ice cooling with 5 cm3 of saturated NH4Cl solution, diluted with 15cm3 of Et2O, and
extracted with 3ꢂ10 cm3 of 0.5 N HCl. The combined aqueous layers were rendered alkaline with
saturated Na2CO3 solution and extracted with 3ꢂ20 cm3 of Et2O. The combined ether layers were
dried with Na2SO4 and evaporated in vacuo. The residue was purified by FC (silica gel, for eluent see
TLC). Yield 176 mg (80%, Ref. [21] 66%, diastereomeric mixture), colourless oil; TLC
(CH2Cl2:MeOH¼ 10:0.3): Rf ¼ 0.33; MS (EI): m=z (%) ¼ 229 (Mþꢄ, 17), 214 (26), 186 (54), 91
1
(100); H NMR: ꢁ ¼ 7.28–7.25 and 7.23–7.19 (2m, each 2arom H), 7.12 (tt, J ¼ 7.1, 1.7 Hz, 1arom
H), 3.54 and 3.39 (2d, each J ¼ 13.3 Hz, each 1H, benzyl–CH2), 2.60–2.51 and 1.79–1.69 (2m, each
2H), 1.62–1.32 (m, 6H), 1.32–1.15 (m, 3H), 1.01 (s, CH3) ppm; 13C NMR: ꢁ ¼ 141.23, 128.43 (2C),
128.09 (2C), 126.39, 60.81, 52.63, 49.30, 44.18, 29.19, 27.57, 26.24, 22.91, 22.30, 2.00ppm.
cis-1-Benzyl-8a-phenyldecahydroquinoline (16b, C22H27N)
Mg 211 mg (8.8mmol)=THF 2 cm3, bromobenzene 1.38g (8.8mmol)=THF 10cm3, 12a 560 mg
(2.2mmol)=toluene 5 cm3; yield 114 mg (17%) colourless oil; TLC (Al2O3, n-hexane: Et2O ¼ 9:1):
Rf ¼ 0.71; MS (EI): m=z (%) ¼ 305 (Mþꢄ, 26), 262 (100), 228 (18), 91 (62); 1H NMR (45ꢁC): ꢁ ¼ 7.72
(d, J ¼ 7.5Hz, 2arom H), 7.32 (br t, J ¼ 7.5 Hz, 2arom H), 7.20–7.14 and 7.13–7.06 (2m, each 3arom
H), 3.45 and 2.98 (2d, each J ¼ 13.6Hz, 2H, benzyl–CH2), 2.59 (br dt, J ¼ 11.9, 2.8 Hz, 1H), 2.42–
2.35 (m, among others J ¼ 11.9Hz, 1H), 2.33–2.26 (m, among others J ¼ 3.2 Hz, 1H), 2.16 (ddd,
J ¼ 14.0, 12.5, 5.8 Hz, 1H), 2.06–1.99 (m, among others J ¼ 14.0 Hz, 1H), 1.92–1.71 (m, 3H), 1.70–
1.61, 1.59–1.45, and 1.37–1.26 (3m, each 2H), 1.18 (tt, J ¼ 12.5, 4.0 Hz, 1H) ppm; 13C NMR (45ꢁC):

Angularly Substituted Perhydro N-Heterocycles by Bruylants Reaction
575
ꢁ ¼ 146.80, 141.67, 128.82 (2C), 128.16 (2C), 127.83 (2C), 127.59 (2C), 126.24, 126.21, 62.85, 54.08,
45.79, 42.19, 28.99, 26.70, 26.09, 23.81, 20.21, 19.88 (br) ppm.
cis-1-Benzyl-8a-(3-methoxyphenyl)decahydroquinoline (16c, C23H29NO)
Mg 2.30g (96.0 mmol)=THF 10cm3, 3-bromoanisol 17.95 g (96.0mmol)=THF 60 cm3, 12a 6.10g
(24.0mmol)=toluene 50 cm3; yield 884 mg (11%) colourless oil; TLC (Al2O3, n-
hexane:Et2O ¼ 9.5:0.5): Rf ¼ 0.65; MS (EI): m=z (%) ¼ 335 (Mþꢄ, 30), 292 (100), 244 (3), 228
1
(23), 201 (11), 91 (56); H NMR (45ꢁC): ꢁ ¼ 7.35–7.27 (m, 2arom H), 7.23 (br t, J ¼ 7.8 Hz, 1arom
H), 7.20–7.13 and 7.12–7.07 (2m, 2 and 3arom H), 6.76 (br dd, J ¼ 7.8, 2.0 Hz, 1arom H), 3.81 (s,
OCH3), 3.48 and 3.00 (2dd, each J ¼ 13.7Hz, each 1H, benzyl–CH2), 2.64–2.56, 2.42–2.33, 2.29–
2.21, 2.20–2.08, and 2.03–1.93 (5m, each 1H), 1.91–1.72 (m, 3H), 1.70–1.60 and 1.59–1.43 (2m, each
13
2H), 1.38–1.33 (m, 3H) ppm; C NMR (45ꢁC): ꢁ ¼ 159.32, 148.78, 141.69, 128.32, 128.14 (2C),
127.86 (2C), 126.20, 121.49, 115.50, 111.17, 62.92, 55.23, 54.11, 45.75, 42.22, 28.96, 26.65, 26.04,
23.78, 20.18 (2C) ppm.
cis-1-Benzyl-7a-(3-methoxyphenyl)octahydro[1]pyrindine (17b, C22H27NO)
Mg 3.20g (133.2mmol)=THF 10 cm3, 3-bromoanisol 24.91 g (133.2mmol)=THF 60 cm3, 13 8.00g
(33.3mmol)=toluene 50cm3; yield 21 mg (0.2%) colourless oil; TLC (Al2O3, n-hexane:Et2O ¼ 9:1):
1
Rf ¼ 0.66; MS (EI): m=z (%) ¼ 321 (Mþꢄ, 34), 292 (100), 278 (10), 214 (13), 201 (11), 91 (62); H
NMR: ꢁ ¼ 7.34 (br t, J ¼ 2.0Hz, 1arom H), 7.28–7.20 (br m, 6arom H), 7.19–7.13 (m, 1arom H), 6.74
(ddd, J ¼ 7.7, 2.5, 1.3Hz, 1arom H), 3.82 (s, OCH3), 3.51 and 2.95 (2d, each J ¼ 13.7Hz, each 1H,
benzyl–CH2), 2.69 (ddt, J ¼ 11.0, 3.4, 1.5 Hz, 1H), 2.31–2.21 (m, 2H), 2.01–1.86 (m, 4H), 1.66–1.55
(m, 3H), 1.45–1.36 (m, 1H), 1.35–1.15 (m, 2H) ppm; 13C NMR: ꢁ ¼ 159.24, 150.84, 140.92, 128.33,
128.22 (2C), 127.92 (2C), 126.31, 119.91, 113.50, 111.31, 72.48, 56.60, 55.16, 47.16, 45.82, 28.26,
28.22, 25.03, 21.24, 20.68 ppm. Hydrochlorid (17b-HCl): colourless, amorphous solid, mp 254ꢁC; 1H
NMR (500MHz, CDCl3): ꢁ ¼ 11.03 (br s, NþH), 7.37–7.28 (m, 8arom H), 6.97 (dd, J ¼ 8.3, 2.0 Hz,
1arom H), 4.17 (d, J ¼ 12.9Hz, 1H), 4.03 (br s, OCH3), 3.65–3.58 and 3.48–3.41 (2m, each 1H), 2.99–
2.87 (m, 2H), 2.78 (dt, J ¼ 12.4, 5.5 Hz, 1H), 2.52–2.44, 2.28, and 2.06–1.93, (3m, each 1H), 1.86–
1.76 and 1.46–1.21 (2m, each 3H) ppm.
cis-1-Benzyl-6a-(3-methoxyphenyl)octahydrocyclopenta[b]pyrrole (18, C21H25NO)
Mg 1.41g (58.9 mmol)=THF 10cm3, 3-bromoanisol 11.02 g (58.92 mmol)=THF 30cm3, 14 3.33g
(14.73 mmol)=toluene 35 cm3; yield 3.53g (78%) colourless oil; TLC (Al2O3, n-hexane:Et2O ¼
1
9.5:0.5): Rf ¼ 0.61; MS (EI): m=z (%) ¼ 307 (Mþꢄ, 33), 278 (100), 264 (20), 91 (60); H NMR:
ꢁ ¼ 7.30–7.22 (m, 5arom H), 7.21–7.15 (m, 1arom H), 7.15 (br t, J ¼ 2.1Hz, 1arom H), 7.09 (br dt,
J ¼ 7.7, 0.7 Hz, 1arom H), 6.76 (br dd, J ¼ 8.1, 2.6 Hz, 1arom H), 3.80 (s, OCH3), 3.44 and 3.23 (2d,
each J ¼ 13.7Hz, each 1H, benzyl–CH2), 2.73 (ddd, J ¼ 9.0, 7.1, 4.4 Hz, 1H), 2.62–2.54 and 2.15–
2.04 (2m, each 2H), 2.00–1.90 (m, 3H), 1.79–1.68 (m, 1H), 1.46–1.36 (m, 2H) ppm; 13C NMR:
ꢁ ¼ 159.34, 149.36, 140.95, 128.66, 128.27 (2C), 128.02 (2C), 126.41, 119.48, 113.23, 111.00, 77.58,
55.14, 53.64, 51.91, 49.79, 34.52, 33.21, 31.84, 26.21ppm.
B. General Procedure for the Synthesis of 7a-Benzyl-derivatives
15g, 15h, 15l, 16a, and 17a
The Grignard reagent was prepared from Mg and benzylbromide in anhydrous THF and the reaction
was completed by heating the mixture to reflux (temperature of the oil bath 70ꢁC). A solution of the

576
E. Reimann et al.
corresponding aminonitrile 11–14 in THF was slowly added over a period of 45 min at 70ꢁC under
vigorous stirring and N2. After the addition was complete the mixture was stirred for an additional 16h
at the same temperature, then quenched with 5 cm3 of saturated NH4Cl solution under ice cooling and
diluted with 30 cm3 of Et2O and 20cm3 of 1 N HCl. The aqueous layer was separated and the organic
phase was extracted with 3ꢂ15cm3 0.5 N HCl. The combined aqueous layers were rendered alkaline
with saturated Na2CO3 solution and extracted with 3ꢂ25cm3 of Et2O. After drying the ether extracts
with Na2SO4 and removing the solvent in vacuo the crude product was crystallized from MeOH. The
solid was collected by filtration, washed with a small volume of ice cold MeOH, and dried in vacuo. If
the crystallization failed to occur or the concentrated mother liquor afforded no further product, the
solvent was removed in vacuo and the residue purified by FC (for eluents see the corresponding
TLC).
cis-(1RS)-7a-Benzyl-1-(1-phenylethyl)octahydroindole (15g, C23H29N,
diastereomeric mixture)
Mg 567.0mg (23.6 mmol)=THF 3 cm3, benzylbromide 4.04 g (23.6 mmol)=THF 10cm3, 11c 1.50g
(5.9mmol)=THF 5 cm3. The residue of the ether extracts was purified by FC (Al2O3, n-
hexane:Et2O ¼ 9.5:0.5). Yield 1.19g (63%) colourless oil; TLC (Al2O3, eluent see FC): Rf ¼ 0.79.
Partial separation of the diastereomers by FC (eluent see TLC, below).
Diastereomer A. Yield 72 mg; TLC (Al2O3, n-hexane:Et2O ¼ 10:0.1): Rf ¼ 0.53; MS (CI): m=z
(%) ¼ 320 (Mþꢄþ1, 63), 228 (100); 1H NMR: ꢁ ¼ 7.41–7.37 and 7.34–7.28 (2m, each 2arom H), 7.24–
7.15 and 7.09–7.05 (2m, 4 and 2arom H), 4.21 (q, J ¼ 6.7 Hz, 1H), 3.10 and 2.82 (2dt, J ¼ 9.5, 5.6 and
9.5, 4.5 Hz, each 1H), 2.64 and 2.58 (2d, each J ¼ 13.8Hz, each 1H, benzyl–CH2), 1.93–1.83, 1.83–
1.75, and 1.74–1.63 (3m, 2, 1, and 1H), 1.60–1.36 (m, 6H), 1.49 (d, J ¼ 6.7 Hz, CH3), 1.21–1.11 (m,
1H) ppm.
Diastereomer B. Yield 53 mg; TLC: Rf ¼ 0.46; MS: same fragmentation and intensities as given for
A; 1H-NMR: ꢁ ¼ 7.41–7.14 (m, 10arom H), 4.22 (q, J ¼ 6.9 Hz, 1H), 3.11–3.01 (m, 2H), 2.88 and 2.61
(2d, each J ¼ 13.2Hz, each 1H, benzyl–CH2), 2.09–1.96 and 1.85–1.75 (2m, each 1H), 1.51–1.24 (m,
7H), 1.48 (d, J ¼ 6.9 Hz, CH3), 1.16–1.06 and 0.97–0.79 (2m, each 1H) ppm.
cis-7a-Benzyl-1-isopropyloctahydroindole (15h, C18H27N)
Mg 288.0 mg (12.0 mmol)=THF 3 cm3, benzylbromide 2.05 g (12.0 mmol)=THF 10cm3, 11d 576 mg
(3.0mmol)=THF 5 cm3. Yield 555 mg (72%) colourless crystals; TLC (n-hexane:Et2O ¼ 10:1):
1
Rf ¼ 0.66; MS (CI): m=z (%) ¼ 258 (Mþꢄþ1, 58), 166 (100); H NMR: ꢁ ¼ 7.26–7.21 and 7.19–
7.14 (2m, 2 and 3arom H), 3.30 (sept, J ¼ 6.6 Hz, 1H), 2.92–2.89 and 2.89–2.83 (2m, each 1H),
2.74 and 2.58 (2d, each J ¼ 13.5 Hz, each 1H, benzyl–CH2), 1.85–1.76 and 1.75–1.68 (2m, each 1H),
1.59 (ddd, J ¼ 13.0, 8.3, 3.5Hz, 1H), 1.54–1.24 and 1.16–1.05 (2m, 7 and 1H), 1.10 and 1.06 (2d, each
J ¼ 6.6 Hz, 2CH3) ppm.
cis-1,7a-Dibenzyloctahydroindole (15l, C22H27N)
Mg 96.0mg (4.0mmol)=THF 3 cm3, benzylbromide 684 mg (4.0mmol)=THF 10cm3, 11a 240 mg
(1.0mmol)=THF 5 cm3. Yield 253 mg (83%) colourless crystals, mp 74ꢁC; TLC (Al2O3, n-hexane):
1
Rf ¼ 0.20; MS (CI): m=z (%) ¼ 306 (Mþꢄþ1, 66), 214 (100), 91 (9); H NMR: ꢁ ¼ 7.39–7.34 and
7.33–7.18 (2m, 2 and 8arom H), 3.84 and 3.64 (2d, each J ¼ 13.8 Hz, each 1H, N-benzyl–CH2), 2.79
and 2.73 (2d, J ¼ 13.9 Hz, each 1H, benzyl–CH2), 2.67 and 2.61 (2dt, J ¼ 9.8, 4.8 and 9.8, 5.2 Hz, each
1H), 1.95–1.74, 1.74–1.33, and 1.29–1.18 (3m, 2, 8, and 1H) ppm; 13C NMR: ꢁ ¼ 140.82, 139.10,

Angularly Substituted Perhydro N-Heterocycles by Bruylants Reaction
577
130.86 (2C), 128.16 (2C), 128.09 (2C), 127.62 (2C), 126.35, 125.78, 64.25, 51.94, 49.00, 38.48, 38.42,
27.71, 27.53, 26.18, 22.72, 22.15 ppm.
cis- and trans-1,8a-Dibenzyldecahydroquinoline (16a, C23H29N)
Mg 151.0 mg (6.3mmol)=THF 3 cm3, benzylbromide 1.08g (6.3mmol)=THF 10cm3, 12a 400 mg
(1.6mmol)=THF 10 cm3. The mother liquor was evaporated and the trans stereomer was separated
from the residue by FC.
cis-16a. Yield 382 mg (76%) colourless crystals, mp 99ꢁC; TLC (CH2Cl2:MeOH¼ 10:0.5):
Rf ¼ 0.73; MS (CI): m=z (%) ¼ 320 (Mþꢄþ1, 45), 228 (100), 91 (17); 1H NMR: ꢁ ¼ 7.40 (br d, J ¼ 7.4 Hz,
2arom H), 7.29 (br t, J ¼ 7.4Hz, 2arom H), 7.27–7.16 (m, 6arom H), 4.08 and 3.20 (2d, each J ¼ 14.1Hz,
each 1H, N-benzyl–CH2), 3.40 and 2.55 (2d, each J ¼ 13.3Hz, each1H, benzyl–CH2), 2.65 (dt, J ¼ 12.2,
3.4 Hz, 1H), 2.62–2.56 (m, 1H), 2.28–2.08 and 2.00–1.94 (2m, 2 and 1H), 1.89–1.78, 1.73–1.63, and
1.58–1.51 (3m, 1, 2, and 1H), 1.41–1.33, 1.33–1.21, and 1.20–1.00 (3m, each 2H) ppm; 13C NMR:
ꢁ ¼ 141.76, 139.98, 130.83 (2C), 128.20 (2C), 128.10 (2C), 127.79 (2C), 126.30, 125.67, 59.16, 52.22,
46.12, 36.35, 35.30, 33.24 (br), 27.41, 26.66, 26.55 (br), 21.40 (br), 21.11 ppm.
trans-16a. Yield 30mg (6%) colourless crystals, mp 86ꢁC; TLC (CH2Cl2:MeOH¼ 10:0.5):
1
Rf ¼ 0.46; MS (CI): m=z (%) ¼ 320 (Mþꢄþ1, 100), 228 (72); H NMR: ꢁ ¼ 7.37–7.08 (m, 10arom
H), 3.55 and 2.91 (2d, each J ¼ 15.4Hz, each 1H, N-benzyl–CH2), 3.35 and 2.79 (2d, each
J ¼ 13.9Hz, each 1H, benzyl–CH2), 3.19 (br t, J ¼ 10.8 Hz, 1H), 2.59–2.52 and 2.24–2.15 (2m, each
1H), 1.86–1.53 and 1.53–1.12 (2m, 7 and 5H) ppm; 13C NMR: ꢁ ¼ 142.21, 139.30, 130.11 (2C),
127.10 (2C), 126.82 (2C), 126.40 (2C), 124.87 (2C), 59.05, 51.57, 46.32, 45.45, 32.32, 28.99, 28.51,
26.50, 25.51, 24.58, 22.23 ppm.
cis-1,7a-Dibenzyloctahydro-1-pyrindine (17a, C22H27N)
Mg 266.0 mg (11.1 mmol)=THF 3 cm3, benzylbromide 1.90 g (11.1 mmol)=THF 10cm3, 13
665 mg (2.8mmol)=THF 10 cm3. Yield 684 mg (78%) colourless crystals, mp 119ꢁC; TLC
1
(n-hexane:Et2O ¼ 10:0.5): Rf ¼ 0.90; MS (CI): m=z (%) ¼ 306 (Mþꢄþ1, 100), 214 (15); H NMR:
ꢁ ¼ 7.37–7.17 (m, 10arom H), 4.06 and 3.24 (2d, each J ¼ 14.6Hz, each 1H, N-benzyl–CH2), 3.14
and 2.73 (2d, each, J ¼ 13.2 Hz, C-benzyl–CH2), 2.58–2.46 (m, 2H), 1.99–1.67 and 1.59–1.32 (2m, 6
and 5H) ppm; 13C NMR: ꢁ ¼ 141.79, 139.82, 130.72 (2C), 128.10 (2C), 128.00 (2C), 127.81 (2C),
126.30, 125.60, 66.76, 54.08, 46.09, 39.23, 33.48, 33.04, 26.92, 23.26, 21.24, 20.79 ppm.
Hydrogenolyses
The mixture of the benzylamine 15–17 (1 molequiv.), MeOH, 2 N HCl (1molequiv.), and 10% Pd–C
was hydrogenated for 3 h at 50ꢁC and 6.5ꢂ106 Pa initial pressure of H2. After centrifuging off the
catalyst and washing with 30 cm3 of MeOH the solvent was evaporated in vacuo. The residue was
dissolved in 10cm3 of Et2O and extracted with 1 N HCl (3ꢂ10cm3). The combined aqueous layers
were rendered alkaline with 32% NaOH solution and extracted with Et2O (3ꢂ10cm3). After drying the
combined ether extracts (Na2SO4) the solvent was removed in vacuo. If necessary, the products were
purified by FC (eluents were the same as used in TLC).
cis-7a-Methyloctahydroindole (15m)
15i or 15k 58 or 61mg (0.25 mmol), 2 N HCl 0.15cm3 (0.3mmol), Pd–C 7 mg, MeOH 5 cm3; yield
30mg (86%) slight yellowish oil; TLC (CH2Cl2:MeOH:NH3 (25%)¼ 100:7:1): Rf ¼ 0.34; MS (EI):
m=z (%) ¼ 139 (Mþꢄ, 17), 124 (38), 96 (100); 1H NMR data are completely in line with those published
in Ref. [21]; 13C NMR: ꢁ ¼ 59.71, 44.38, 42.72, 33.69, 29.99, 26.73, 26.19, 22.92, 22.04 ppm.

578
E. Reimann et al.
cis-8a-Benzyldecahydroquinoliniumchlorid (16d-HCl, C16H24ClN)
16a 100 mg (0.31 mmol), 2 N HCl 0.15cm3 (0.3mmol), Pd–C 10 mg, MeOH 5 cm3; the residue was
dissolved in 5 cm3 of Et2O and ether saturated with HCl. After removing the solvent the residue was
crystallized from EtOAc. Yield 75mg (91%) colourless crystals, mp 231ꢁC (EtOAc); TLC
1
(CH2Cl2:MeOH:NH3 (25%) ¼ 100:9:0.5): Rf ¼ 0.39; MS (CI): m=z (%) ¼ 230 (100), 138 (63); H
NMR (50ꢁC): ꢁ ¼ 9.37 and 8.65 (2br s, each 1H, NþH2), 7.36–7.25 (m, 5arom H), 3.54 and 3.13
(2br d, each J ¼ 13.2 Hz, each 1H, benzyl–CH2), 3.46–3.31 (m, 2H), 2.21–1.90, 1.86–1.68, 1.65–1.48,
and 1.15–1.03 (4m, 5, 3, 4, and 1H) ppm; 13C NMR (CDCl3): ꢁ ¼ 135.00, 131.11 and 128.52 (each
2C), 127.26, 60.35, 39.96, 39.82, 34.16, 31.50 (br), 26.29, 24.21, 23.82 (br), 20.63, 18.08 (br) ppm.
cis-8a-(3-Methoxyphenyl)-decahydroquinoline (16e, C16H23NO)
16c 533 mg (1.59 mmol), 2 N HCl 0.8 cm3, Pd–C 65mg, MeOH 8 cm3; yield 372 mg (95%) colourless
oil; TLC (CH2Cl2:MeOH:NH3 (25%) ¼ 100:5:1): Rf ¼ 0.21; MS (EI): m=z (%) ¼ 245 (Mþꢄ, 24), 202
(100); 1H NMR (45ꢁC): ꢁ ¼ 7.26 (t, J ¼ 8.0 Hz, 1arom H), 7.10–7.05 (m, 2H), 6.77–6.73 (ddd, J ¼ 8.0,
2.6, 0.9 Hz, 1arom H), 3.81 (s, OCH3), 2.85–2.79 (m, 1H), 2.74–2.66, 2.45–2.31, 2.07–1.97, 1.82–
13
1.25, and 1.20–1.11 (5m, 1, 1, 1, 11, and 1H) ppm; C NMR (40ꢁC): ꢁ ¼ 160.13, 150.23, 129.34,
118.42, 112.62, 110.66, 58.39, 55.26, 43.09 (br), 42.17, 35.90, 27.27, 26.74, 25.98, 22.48, 21.31 ppm.
cis-7a-Benzyloctahydro-1-pyrindine (17c, C15H21N)
17a 90mg (0.3mmol), 2 N HCl 0.15 cm3 (0.3mmol), Pd–C 9 mg, MeOH 5 cm3; yield 58mg (91%)
colourless oil; TLC (CH2Cl2:MeOH:NH3 (25%) ¼ 100:9:0.5): Rf ¼ 0.39; MS (CI): m=z (%) ¼ 216
1
(Mþꢄþ1, 100), 124 (48); H NMR: ꢁ ¼ 7.31–7.27, 7.24–7.20, and 7.19–7.17 (3m, 2, 1, and 2arom
H), 3.19 and 2.56 (2d, each J ¼ 13.3 Hz, each 1H, benzyl–CH2), 2.97 (ddd, J ¼ 12.1, 10.6, 3.0 Hz, 1H),
2.85–2.81 (m, 1H), 2.55 (br s, NH), 1.90–1.68, 1.67–1.53, and 1.44–1.37 (3m, 6, 3, and 2H) ppm;
13C NMR: ꢁ ¼ 138.59, 130.04, 128.05, 126.06, 66.81, 41.76, 41.04, 40.68, 37.40, 27.92, 23.63, 21.10,
20.46 ppm; 17c-HCl: mp 185.5ꢁC (EtOAc=Et2O).
trans-1-Benzoyloctahydroquinoline-8a-carbonitrile (20, C17H20N2O)
To a solution of 200 mg of 12b (1.23 mmol) and 130 mg of Et3N (1.29 mmol) in 5 cm3 of CHCl3 was
added a solution of 172 mg of benzoylchloride (1.23mmol) in 2 cm3 of CHCl3 and the mixture was
heated under reflux for 1.5 h. The cold solution was diluted with 10cm3 of CHCl3 and consecutively
washed with 2ꢂ10 cm3 of H2O and 10cm3 of saturated NH4Cl solution. The organic layer was dried
(Na2SO4) and evaporated. The residue first was purified by FC (silica gel, CH2Cl2), then recrystallized
from n-hexane. Yield 116 mg (35%) colourless crystals, mp 142ꢁC; TLC (CH2Cl2): Rf ¼ 0.38; IR
(KBr): ꢂꢀ¼ 2229 (CN), 1661 and 1636 (C¼O) cmꢃ1; MS (CI): m=z (%) ¼ 269 (Mþꢄþ1, 100), 242 (56),
1
105 (10); H NMR: ꢁ ¼ 7.61–7.56, 7.53–7.44, and 7.43–7.38 (3m, 2, 1, and 2arom H), 3.66–3.58,
3.39–3.32, and 3.31–3.23 (3m, each 1H), 1.92–1.65, 1.64–1.43, and 1.41–1.28 (3m, 8, 3, and 1H)
ppm; 13C-NMR: ꢁ ¼ 174.19, 136.05, 131.14, 128.56, 128.27, 118.13, 60.42, 47.06, 42.88, 35.59, 30.27,
26.81, 25.16, 23.56. 23.32 ppm.
cis-(1-Benzyloctahydroindol-7a-yl)phenylmethanone (21, C22H25NO)
To a solution of 560 mg (2.3mmol) of 11a in 5 cm3 of cyclohexane:Et2O (7:3) was added 5 cm3 of
1.8 M phenyllithium (9.0mmol) in the same solvent. After stirring for 16h at ambient temperature the
mixture was quenched with 3 cm3 of saturated NH4Cl solution and diluted with 20cm3 of 0.5 N HCl.
The aqueous layer was washed with 2ꢂ10cm3 of Et2O, rendered alkaline with saturated Na2CO3
solution and extracted with 3ꢂ30 cm3 of Et2O. The ether extracts were dried (Na2SO4) and evaporated

Angularly Substituted Perhydro N-Heterocycles by Bruylants Reaction
579
in vacuo. The residue was purified by FC (silica gel, n-hexane:Et2O ¼ 9:1) giving a colourless oil,
which was crystallized from hot MeOH. The colourless solid was collected by filtration, washed with a
small volume of ice cold MeOH, and dried in vacuo. Yield 128 mg (17%), mp 100ꢁC (MeOH);þTꢄLC
(for eluent see FC): Rf ¼ 0.77; IR (KBr): ꢂꢀ¼ 1673 (C¼O) cmꢃ1; MS (CI): m=z (%) ¼ 320 (M þ1,
100), 214 (41); 1H NMR: ꢁ ¼ 8.34–8.31 (m, 2arom H), 7.50 (tt, J ¼ 7.4, 1.3 Hz, 1arom H), 7.42–7.37
and 7.36–7.15 (2m, 2 and 5arom H), 3.79 and 3.43 (2d, each J ¼ 12.9Hz, each 1H, benzyl–CH2), 3.12
(ddd, J ¼ 9.6, 7.8, 7.0 Hz, 1H), 3.00–2.91 (m, 1H), 2.61 (dt, J ¼ 9.6, 8.1Hz, 1H), 2.36–2.30 (m, 1H),
1.89 (m, 2H), 1.80–1.71 and 1.60–1.28 (2m, 1 and 6H) ppm; 13C NMR: ꢁ ¼ 204.85, 139.63, 137.39,
131.60, 129.72 (2C), 128.82 (2C), 128.10 (2C), 127.80 (2C), 126.71, 73.84, 54.14, 49.85, 42.57, 26.54,
25.97, 22.98, 22.73, 20.35 ppm.
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[14] Vierhapper FW, Eliel EL (1977) J Org Chem 42: 51
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