N-acyliminium cyclization as an approach for an asymmetric synthesis of the pyrrolo[2,1-a]benzazepine ring system

Article abstract of DOI:10.1080/00397911.2010.532900

In this article, we report a facile asymmetric synthesis of the pyrrolo[2,1-a]ben-zazepine ring system based around a stereoselective N-acyliminium cyclization of a novel chiral lactam template. Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2010.532900

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N-Acyliminium Cyclization as an
Approach for an Asymmetric Synthesis
of the Pyrrolo[2,1-a]benzazepine Ring
System
Steven M. Allin a , Joannah M. R. Towler b , Mark R. J. Elsegood b ,
Basu Saha c & Philip C. Bulman Page d
a School of Physical and Geographical Sciences, Keele University,
Keele, United Kingdom
b Department of Chemistry, Loughborough University, Loughborough,
United Kingdom
c Department of Chemical Engineering, Loughborough University,
Loughborough, United Kingdom
d School of Chemistry, University of East Anglia, Norwich, United
Kingdom
Accepted author version posted online: 30 Aug 2011.Version of
record first published: 11 Nov 2011.
To cite this article: Steven M. Allin , Joannah M. R. Towler , Mark R. J. Elsegood , Basu Saha & Philip
C. Bulman Page (2012): N-Acyliminium Cyclization as an Approach for an Asymmetric Synthesis of the
Pyrrolo[2,1-a]benzazepine Ring System, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 42:6, 872-882
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Synthetic Communications1, 42: 872–882, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.532900
N-ACYLIMINIUM CYCLIZATION AS AN APPROACH
FOR AN ASYMMETRIC SYNTHESIS OF THE
PYRROLO[2,1-a]BENZAZEPINE RING SYSTEM
Steven M. Allin,1 Joannah M. R. Towler,2
Mark R. J. Elsegood,2 Basu Saha,3 and
Philip C. Bulman Page4
1School of Physical and Geographical Sciences, Keele University,
Keele, United Kingdom
2Department of Chemistry, Loughborough University, Loughborough,
United Kingdom
3Department of Chemical Engineering, Loughborough University,
Loughborough, United Kingdom
4School of Chemistry, University of East Anglia, Norwich, United Kingdom
GRAPHICAL ABSTRACT
Abstract In this article, we report a facile asymmetric synthesis of the pyrrolo[2,1-a]ben-
zazepine ring system based around a stereoselective N-acyliminium cyclization of a novel
chiral lactam template.
Keywords Alkaloid; aminoalcohol; asymmetric; cyclization; N-acyliminium
INTRODUCTION
Our research group, and others, have had considerable success in recent years
developing asymmetric routes to a wide range of important heterocyclic templates,
based around the development of a highly diastereoselective N-acyliminium cycliza-
tion strategy.[1] Our own recent applications of this methodology in natural product
synthesis have included targets from the erythrina group of alkaloids[1h,i] and several
indole alkaloids.[1a,c,d,f] Given our success in the synthesis of the pyrroloisoquinoline
ring system, found within the erythrina alkaloids,[1h,i] we decided to investigate the
application of asymmetric N-acyliminium cyclization as an approach to the analogous
Received September 1, 2010.
Address correspondence to Steven M. Allin, School of Physical and Geographical Sciences, Keele
University, Keele, ST5 5BG, UK. E-mail: s.m.allin@chem.keele.ac.uk
872

PYRROLO[2,1-a]BENZAZEPINE
873
chiral pyrrolo[2,1-a]benzazepine ring system, 1, the core of which is found as a subunit
in the homoerythrina alkaloids. This natural product family includes dyshomoerythr-
ine, 2, which has been isolated from the New Zealand silver pine and shown to be
active against several important agricultural pests.[2] Although several approaches
for the synthesis of homoerythrina alkaloids (and structurally simpler pyrrolo
[2,1-a]benzazepines) have been reported,[3] few involve the intermediacy of an
N-acyliminium intermediate in an asymmetric cyclization reaction as an approach
to construct the central seven-membered ring: Katritzky[4a] reported a titanium
tetrachloride–induced cyclization of a benzotriazole derivative to yield the racemic
6,7,5-ring system, 1 (Scheme 1), and Padwa investigated the cyclization of furan onto
an in situ–generated N-acyliminium species.[4b] Neither of these reports addressed the
issue of asymmetric control in the cyclization step. Although not directly related to
the 6,7,5-ring system under investigation herein, Flynn et al. were able to achieve dia-
stereocontrol in the N-acyliminium cyclization of the chiral phenylalanine-derived
enamide 3 to yield a 6,7,6-ring target, 4 (Scheme 1).[5]
Our approach began with the synthesis of the novel bicyclic lactam, 5, which
would serve as the N-acyliminium precursor in the key cyclization reaction. As high-
lighted in Scheme 2, condensation of S-2-amino-4-phenylbutan-1-ol with succinic
anhydride under Dean–Stark conditions furnished the intermediate imide in good
yield. The imide was then subjected to a reduction–cyclization cascade to deliver
the desired bicyclic lactam, 5, as a single diastereoisomer in good yield. The stereo-
chemistry of compound 5 was established by nuclear Overhauser effect (NOE) studies
and was found to be as expected from our previous studies on related templates.[1,6]
(The protons at positions 3 and 7a do not show a positive NOE effect toward each
other, suggesting a trans relationship between them. This result is as expected based
on previous examples of a range of other bicyclic lactam templates prepared in an
analogous fashion by our group.[1,6]
)
With compound 5 in hand, we turned our attention to the key N-acyliminium
cyclization reaction. In our previous work, we have investigated the use of a range
of activators and reaction conditions for this type of cyclization, including both Lewis
and protic acids, and, depending on the structure of the bicyclic lactam, the reaction
temperature required to achieve cyclization with a good level of diastereoselectivity. In
the case of bicyclic lactam 5, use of titanium tetrachloride (ꢀ78 ꢁC, dichloromethane,
Scheme 1. Chiral pyrrolo[2,1-a]benzazepine targets.

874
S. M. ALLIN ET AL.
Scheme 2. Synthesis of the key N-acyliminium precursor.
DCM), boron trifluoride–diethyl etherate (ꢀ78 ꢁC, DCM), or 2 M HCl (rt, EtOH) as
the activator for the cyclization reaction resulted in either re-isolation of the starting
material or formation of complex, intractable mixtures of products.
The desired cyclization was finally achieved in almost quantitative yield (97%)
by treating lactam 5 with 1.5 eq. of titanium tetrachloride in dry dichloromethane at
ꢀ96 ꢁC, followed by slow warming to room temperature (Scheme 3). Under these
conditions, the desired pyrrolo[2,1-a]benzazepinone was formed as a 4:1 mixture
of separable diastereoisomers, 6a and 6b. The relative stereochemistries of both 6a
and 6b were established by NOE studies on the purified individual compounds.
(For compound 6b, the proton at position 11b shows a positive NOE with the proton
at position 5, confirming the cis relationship between these protons. The protons at
positions 5 and 11b do not show a positive NOE effect toward each other, suggesting
a trans relationship between them in compound 6a.)
The sense of stereochemical induction observed in this cyclization—favoring
the formation of the anti diastereoisomer 6a (with respect to the H-atoms at the
chiral centers)—was found to match that observed in our previous work on related
Scheme 3. Stereoselective cyclization to a pyrrolo[2,1-a]benzazepine target.

PYRROLO[2,1-a]BENZAZEPINE
875
Scheme 4. Removal of the hydroxymethyl substituent.
ring systems.[7] This novel asymmetric cyclization, setting up a central seven-
membered ring, can therefore be rationalized by application of the conformational
models that we have developed previously.[7]
Cyclization of 5 to 6 was more difficult to achieve than the corresponding
cyclizations undertaken previously in our laboratory, but this was not unexpected
given that we were attempting to generate a seven-membered ring in the current
study. The fact that the cyclization was found to proceed only at a lower temperature
(i.e., ꢀ96 ꢁC rather than ꢀ78 ꢁC) with the same Lewis acid is intriguing, and we sug-
gest that the lower temperature acts to promote the desired cyclization of the aro-
matic ring to yield the 6,7,5-product 6 (presumably the kinetic product) by
slowing the reversible reformation of the 5,5-bicyclic lactam 5 (thermodynamic pro-
duct). At higher temperatures, although N-acyliminium ion generation is to be
expected, the preferred reaction is simply for the oxyanion, 5a, to cyclize to regener-
ate the starting material, 5.
To demonstrate the potential utility of this work, we applied a previously
developed route for removal of the hydroxymethyl auxiliary tether from the major
diasteroisomer, 6a.[1e,h,i] Oxidation of the primary alcohol moiety in 6a to yield an
intermediate aldehyde was followed by a rhodium-induced decarbonylation to
deliver the target amide, R-(þ)-7 (Scheme 4).
The structure of the homoerythrina alkaloids, exemplified by dyshomoerythrine 2,
is characterized by a tetracyclic ring skeleton. With a successful synthesis of a
nonracemic pyrrolo[1,2-a]benzazepinone target having been achieved, we became more
Scheme 5. Unexpected formation and x-ray crystal structure of conjugated lactam 10.

876
S. M. ALLIN ET AL.
Scheme 6. Proposed mechanism for formation of the conjugated lactam 10.
ambitious and attempted to access this tetracyclic ring system through an analogous
procedure. To this end, novel tricyclic lactam 8 was prepared as highlighted in
Scheme 5 and subjected to a range of typical reaction conditions to induce the cycliza-
tion (Scheme 5).
Unfortunately, the desired target 9 could not be obtained under any reaction
conditions tried by us, including both Lewis and protic acid activation. Instead the
only identifiable product to be observed was formation of a single diastereoisomer
of the conjugated lactam 10, in up to 80% yield. The structure of 10 was confirmed
by x-ray crystallography using synchrotron radiation (Scheme 5).[8] Formation of
10 can be explained by initial formation of the expected N-acyliminium intermediate,
followed by a series of proton losses and corresponding double bond migrations from
the N-acyliminium species, through the enamide, to the more favored conjugated
lactam, 10 (Scheme 6). Interestingly, the formation of an analogous conjugated amide
as a by-product in a related N-acyliminium cyclization reaction was recently observed
by Tietze, albeit in the racemic series.[9]
In conclusion, we have developed a new and facile asymmetric synthesis of the
pyrrolo[2,1-a] benzazepine ring system based around a stereoselective N-acyliminium
cyclization reaction of a novel template.
EXPERIMENTAL
˚
All solvents were dried, distilled, and stored over 4-A molecular sieves prior to
use. Analytical thin-layer chromatography (TLC) was carried out using aluminium-
backed plates coated with 0.2 mm silica. Plates were visualised under ultraviolet
(UV) light (at 254 nm) or by staining with either potassium permanganate solution
or phosphomolybdic acid. Flash column chromatography was carried out using
Merck Kieselgel (70–230 Mesh ASTM). Samples were applied as saturated solutions
in an appropriate solvent or preadsorbed onto the minimum quantity of silica. Hand
bellows were used to apply pressure when required at the column. Infrared (IR) spec-
tra were recorded in the range from 4000 to 600 cmꢀ1. Solid samples were run as
nujol mull and liquids as thin films. Nuclear magnetic resonance (NMR) spectra
(1H and 13C) were recorded using either Bruker AC-250 or DPX-400 instruments.

PYRROLO[2,1-a]BENZAZEPINE
877
Multiplicities were recorded as broad peaks (br), singlets (s), doublets (d), triplets (t),
and multiplets (m). All NMR samples were made up in deuterated chloroform with
all values quoted in parts per million (ppm) relative to tetramethylsilane (TMS) as
internal reference, unless otherwise stated. Coupling constants (J values) are
reported in hertz (Hz). Diastereoisomer ratios were calculated from the integration
of suitable peaks in the proton NMR.
(S)-2-Amino-4-phenylbutan-1-ol
(S)-Homophenylalanine hydrochloride salt (2.44 g, 11.34 mmol) was dissolved
in the minimum amount of methanol. Sodium carbonate (1.20 g, 11.34 mmol)
was added in one portion, and the mixture was allowed to stir for 5 min. The
resulting solution was filtered and evaporated under reduced pressure to yield
(S)-homophenylalanine as a white solid, (1.90 g, 98%). Trimethylsilylchloride
(5.39 mL, 42.46 mmol) was added to lithium borohydride (10.61 mL, 21.23 mmol)
in tetrahydrofuran (THF; 30 ml) over 5 min under an atmosphere of nitrogen.
(S)-Homophenylalanine (1.90 g, 10.61 mmol) was cautiously added to the resulting
mixture, and the reaction mixture was stirred at room temperature for 24 h. After
24 h, methanol (30 mL) was cautiously added dropwise, and the volatiles were
removed using a rotary evaporator. The residue was treated with 20% potassium
hydroxide solution (75 mL) and extracted into dichloromethane (3 ꢂ 50 mL). The
organic extracts were combined, dried over anhydrous magnesium sulfate, and
filtered, and the solvent was removed under reduced pressure to yield the target
compound as a colorless oil (1.31 g, 75%):
[10]
1
IR (thin film, CH2Cl2) 3343 cmꢀ1; H NMR
20
½aꢃD ¼ ꢀ4:7 (c 0.5, MeOH);
(MeOD, 400 MHz) 1.48–1.55 (1 H, m), 1.62–1.69 (1 H, m), 2.52–2.73 (3 H, m),
3.19–3.30 (1 H, m), 3.45–3.49 (1 H, m), 7.03–7.17 (5 H, m); 13C NMR (CDCl3,
100 MHz) 32.5, 36.1, 52.4, 66.5, 126.0, 128.3, 128.3, 128.5, 128.5, 141.7; HRMS
(EI) 165 (Mþ, 5%), 166 (MHþ, 100%). Calcd. for C10H15NO: 165.11536; found:
165.11516.
(S)-1-(1-Hydroxy-4-phenylbutan-2-yl)pyrrolidine-2,5-dione
Succinic anhydride (0.48 g, 4.84 mmol) and (S)-2-amino-4-phenylbutan-1-ol
(0.80 g, 4.84 mmol) were stirred in toluene (100 mL) under an atmosphere of nitrogen.
Triethylamine (1 mL) was added to the solution, and the mixture was heated at reflux
for 18 h. After this time, the reaction was cooled to room temperature, and solvent
was removed by rotary evaporation to yield a brown oil. The crude product was
adsorbed onto silica gel and chromatographed using silica gel as absorbent and ethyl
acetate as eluent to produce a colorless solid (0.71 g, 60%): mp 74–76 ꢁC; ½aꢃD ꢀ 96
20
1
(c 0.05, CH2Cl2); IR (thin film, CH2Cl2) 3387, 1766, 1692 cmꢀ1; H NMR (CDCl3,
400 MHz) 2.00–2.08 (1 H, m), 2.30–2.58 (6 H, m), 2.76–2.83 (2 H, m), 3.76 (1 H, dd,
J 4.0, 12.0), 3.94–3.98 (1 H, m), 4.26–4.32 (1 H, m), 7.16–7.29 (5 H, m); 13C NMR
(CDCl3, 100 MHz) 27.9, 28.0, 32.8, 54.5, 63.2, 63.7, 126.1, 128.3 (2C), 128.4 (2C),
140.8, 178.3 (2C); HRMS (EI) 248 (MHþ, 100%). Calcd. for C14H18NO3: 248.1287
(MHþ); found: 248.1282.

878
S. M. ALLIN ET AL.
(3S,7aR)-3-Phenethyltetrahydropyrrolo[2,1-b]oxazol-5(6H)-one, 5
(S)-1-(1-Hydroxy-4-phenylbutan-2-yl)pyrrolidine-2,5-dione (1.68g, 6.82mmol)
was dissolved in absolute ethanol (30 mL) and cooled to 0 ꢁC. Sodium borohydride
(2.58 g, 68.20 mmol) was then added with stirring. A 2 M solution of HCl in absolute
ethanol (3.40 mL, 6.82mmol) was then slowly added via syringe over a 3-h period.
The resulting solution was acidified to pH 1–3 by addition of a 2 M solution of HCl
in absolute ethanol over a 15-min period. This afforded a white suspension, which
was stirred for a further 20h. The reaction was quenched with sodium hydrogen car-
bonate and extracted with dichloromethane (3ꢂ 30mL). The dichloromethane layers
were then combined and dried over anhydrous magnesium sulfate, and solvent was
removed by rotary evaporation to yield the target cyclized compound as a single dia-
stereoisomer, which was purified by column chromatography using silica gel as absorb-
20
ent and ethyl acetate as eluent to yield a colorless oil (0.89 g, 57%): ½aꢃD þ 16 (c 0.12,
MeOH), IR (thin film, CH2Cl2) 1682, 1450cmꢀ1 1H NMR (CDCl3, 400 MHz)
;
1.74–1.89 (3 H, m), 2.07–2.10 (1 H, m), 2.36–2.40 (1H, m), 2.52–2.57 (1 H, m),
2.63–2.78 (2H, m), 3.50–3.54 (1 H, m), 4.08–4.11 (1H, dd, J 2.4, 6.0), 4.19–4.23 (1 H,
m), 5.12 (1 H, dd, J 2.0, 6.0), 7.18–7.31 (5 H, m); 13C NMR (CDCl3, 100 MHz) 24.2,
31.6, 32.8, 36.0, 54.9, 72.6, 91.6, 126.0, 128.3, 128.4, 128.5 (2C), 141.4, 179.8; HRMS
(EI) 232 (MHþ, 100%). Calcd. for C14H18NO2: 232.1338 (MHþ); found: 232.1333.
5-(Hydroxymethyl)-5,6,7,11b-tetrahydro-1H-benzo[c]pyrrolo[1,2-a]
azepin-3(2H)-one, 6
(3S,7aR)-3-Phenethyltetrahydropyrrolo[2,1-b]oxazol-5(6H)-one,
5
(0.37 g,
1.60 mmol), was dissolved in anhydrous dichloromethane (25 mL) under a nitrogen
atmosphere and cooled to ꢀ96 ꢁC. Titanium tetrachloride (0.26 mL, 2.40 mmol)
was then slowly added via syringe over a 30-min period. The reaction was allowed
to reach room temperature and stirred for a further 20 h. The reaction was quenched
with aqueous ammonium chloride and extracted with dichloromethane (3 ꢂ 30 ml).
The dichloromethane extracts were then combined and dried over anhydrous
magnesium sulfate, and the solvent was removed by rotary evaporation to yield the
target cyclized compound as a 4:1 mixture of diastereoisomers, which were separated
by column chromatography using silica gel as absorbent and 10% methanol in
dichloromethane as eluent to yield a white solid, 6a, and opaque oil, 6b, in a combined
yield of 0.36 g (97%).
(5S,11bR)-5-(Hydroxymethyl)-5,6,7,11b-tetrahydro-1H-benzo[c]pyrrolo
[1,2-a]azepin-3(2H)-one, 6a. Mp 90–92 ꢁC; [a]D þ 296 (c 0.05, CHCl3); IR (thin
1
film, CH2Cl2) 3386, 2926, 1660 cmꢀ1; H NMR (CDCl3, 400 MHz) 1.48–1.57 (1 H,
m), 2.08–2.24 (2 H, m), 2.40–2.44 (2 H, m), 2.48–2.56 (1 H), 2.63–2.68 (1 H, m),
2.91 (1 H, t, J 12.0), 3.53–3.65 (2 H, m), 3.91 (1 H, br.s), 4.58–4.66 (1 H, m), 5.06–
5.28 (1 H, m), 7.11–7.20 (4 H, m); 13C NMR (CDCl3, 100 MHz) 27.9, 28.6, 30.4,
30.6, 52.2, 59.1, 63.0, 126.5 (2C), 127.2, 130.5, 139.5, 140.2, 176.7; HRMS (EI)
232 (MHþ, 100%). Calcd. for C14H18NO2: 232.1338 (MHþ); found: 232.1333.
(5S, 11bS)-5-(Hydroxymethyl)-5,6,7,11b-tetrahydro-1H-benzo[c]pyrrolo
20
[1,2-a]azepin-3(2H)-one, 6b. ½aꢃD ꢀ 306:7 (c 0.03, CHCl3); IR (thin film, CH2Cl2)

PYRROLO[2,1-a]BENZAZEPINE
879
1
3379, 2925, 1659 cmꢀ1; H NMR (CDCl3, 400 MHz) 1.59–1.66 (1 H, m), 2.06–2.12
(1 H, m), 2.46–2.53 (2 H, m), 2.60–2.69 (3 H, m), 2.87–2.92 (1 H, m), 3.32–3.35
(1 H, m), 3.72–3.74 (1 H, m), 4.01–4.04 (1 H, d, J 12.8), 4.94 (1 H, dd, J 7.2, 9.2),
5.54 (1 H, d, J 10.8), 7.08–7.27 (4 H, m); 13C NMR (CDCl3, 100 MHz) 26.3, 30.0,
30.3, 31.8, 56.9, 62.8, 67.5, 127.1, 127.3, 128.2, 131.1, 137.3, 138.5, 176.2; HRMS
(EI) 232 (MHþ, 100%). Calcd. for C14H18NO2: 232.1338 (MHþ); found: 232.1332.
(5S, 11bR)-3-Oxo-2,3,5,6,7,11b-hexahydro-1H-benzo[c]pyrrolo[1,2-a]
azepine-5-carbaldehyde
Dess Martin periodinane (0.31 g, 0.74 mmol) was added to a solution of
(5S,11bR)-5-(hydroxymethyl)-5,6,7,11b-tetrahydro-1H-benzo[c]pyrrolo[1,2-a]azepin-
3(2H)-one, 6a (0.25 g, 0.74 mmol), in dichloromethane (40 ml) under an atmosphere of
nitrogen. The resulting mixture was allowed to stir at room temperature for 2 h. After
2 h, the solvent was removed under reduced pressure, and the residue was suspended in
diethyl ether (20 mL) and washed with aqueous sodium hydrogen carbonate (100 mL),
containing sodium thiosulfate (25 g), followed by saturated brine (20 mL). The diethyl
ether layer was dried over anhydrous magnesium sulfate, and solvent was removed by
rotary evaporation to yield a brown oil, which was adsorbed onto silica and purified
by column chromatography using silica gel as absorbent and ethyl acetate as eluent to
yield a light brown oil (96 mg, 60%). Oxidation to the aldehyde was accompanied by
some epimerization of the a-amino aldehyde stereocentre, as previously observed on
following this route in other related studies.[1i] The data of the major diastereoisomer
are taken from the crude mixture of aldehyde diastereoisomers (2:1 ratio):
20
½aꢃD þ 182:8 (c 0.07, CHCl3);
1
IR (thin film, CH2Cl2) 2926, 1750, 1683 cmꢀ1; H NMR (400 MHz, CDCl3)
2.05–2.88 (8 H, m), 5.04–5.12 (2 H, m), 7.12–7.27 (4 H, m), 9.59 (1 H, dd, J 12.8);
13C NMR (100 MHz, CDCl3) 25.4, 26.6, 30.0, 30.5, 59.6, 63.7, 127.0, 127.4, 128.1,
130.4, 137.7, 140.2, 175.3, 199.3; HRMS (EI) 230 (MHþ, 100%). Calcd. for
C14H16NO2: 230.1181 (MHþ); found: 230.1177.
(R)-5,6,7,11b-Tetrahydro-1H-benzo[c]pyrrolo[1,2-a]azepin-3(2H)-one, 7
[Bis(triphenylphosphine)]rhodium (I) carbonyl chloride (14 mg, 0.02 mmol) was
added to anhydrous xylene (10 mL) under a nitrogen atmosphere. The mixture was
then stirred at 80 ꢁC for 15 min. 1,3-Bis(diphenylphosphino)propane (19 mg,
0.1 mmol) was added, and the mixture was heated at 80 ꢁC for 30 min. To the stirring
mixture was added (5S,11bR)-3-oxo-2,3,5,6,7,11b-hexahydro-1H-benzo[c] pyr-
rolo[1,2-a]azepine-5-carbaldehyde (90 mg, 0.39 mmol), and the mixture was heated
under reflux for 240 h. After 240 h, the solvent was removed under reduced pressure,
and the crude product was adsorbed onto silica gel and chromatographed using silica
gel as absorbent and ethyl acetate as eluent to yield a brown oil (45 mg, 57%):
ꢀ1
;
1H NMR
20
½aꢃD þ 12 (c 0.70, CHCl3); IR (thin film, CH2Cl2) 2926, 1679 cm
(CDCl3, 400 MHz) 1.73–1.79 (1 H, m), 2.00–2.05 (1 H, m), 2.17–2.23 (1 H, m),
2.36–2.51 (3 H, m), 2.64–2.70 (1 H, m), 2.92–2.99 (2 H, m), 4.10–4.16 (1 H, m),
4.83–4.86 (1 H, t, J 8.4), 7.12–7.27 (4 H, m); 13C NMR (CDCl3, 100 MHz) 25.7,
28.0, 31.0, 31.2, 39.6, 64.1, 126.5, 126.8, 128.4, 132.1, 138.6, 139.1, 174.3; HRMS
(EI) 202 (MHþ, 100%). Calcd. for C13H16NO: 202.1233 (MHþ); found: 202.1226.

880
S. M. ALLIN ET AL.
2-(2-Oxocyclohexyl)ethanoic Acid[1i]
Ethyl-2-cyclohexanoate (2.00 g, 10.86 mmol) was dissolved in a mixture of THF
(20 mL) and water (10 mL). Lithium hydroxide (0.70 g, 16.28 mmol) was added, and
the mixture was stirred at room temperature for 20 h. The reaction mixture was
concentrated, resuspended in water (30 mL), and acidified to pH 3 by careful addition
of aqueous 1 M HCl. The aqueous layer was then extracted into ethyl acetate
(3 ꢂ 40 mL) and dried over anhydrous magnesium sulfate, and the solvent was
removed under reduced pressure to afford a colorless oil (1.66 g, 98%): IR (thin
1
film, CH2Cl2) 3365, 1616 cmꢀ1; H NMR (400 MHz, CDCl3) 1.38–2.87 (11 H, m);
13C NMR (100 MHz, CDCl3) 25.2, 27.8, 33.8, 34.3, 41.8, 46.9, 179.5, 211.2; HRMS
(EI) 157 (MHþ, 100%). Calcd. for C8H13O3: 157.0865 (MHþ); found: 157.0857.
(3S,6aS,10R)-3-Phenethylhexahydro-2H-oxazolo[3,2-i]indol-5
(3H)-one, 8
(S)-2-Amino-4-phenylbutan-1-ol (0.30 g, 1.90 mmol) and 2-(2-oxocyclohexyl)
ethanoic acid (0.31 g, 1.90 mmol) were dissolved in toluene (100 mL) and refluxed
under Dean–Stark conditions for 48 h. After 48 h, the solution was allowed to cool
to room temperature, and the solvent was removed under reduced pressure. The
crude product was adsorbed onto silica gel and chromatographed using silica gel
as absorbent and a 3:1 mixture of ethyl acetate and light petroleum as eluent to yield
20
a yellow oil (0.29 g, 55%): ½aꢃD þ 89:4 (c 0.47, CHCl3); IR (thin film, CH2Cl2)
1
1707 cmꢀ1; H NMR (CDCl3, 400 MHz) 1.39–1.83 (8 H, m), 1.89–1.99 (2 H, m),
2.31–2.45 (2 H, m), 2.60–2.79 (3 H, m), 3.82–3.86 (1 H, m), 4.02–4.08 (1 H, m),
4.15–4.18 (1 H, m), 7.17–7.30 (5 H, m); 13C NMR (CDCl3, 100 MHz) 19.8, 20.8,
25.3, 32.8, 33.0, 37.0, 39.2, 41.8, 54.6, 72.6, 99.7, 126.0, 128.4 (4C), 141.5, 176.6;
HRMS (FAB) 286 (MHþ, 100%). Calcd. for C18H24NO2: 286.18070 (MHþ); found:
286.18097.
(S)-1-((R)-1-Hydroxy-4-phenylbutan-2-yl)-5,6,7,7a-tetrahydro-1H-
indol-2(4H)-one, 10
(3S,6aS,10R)-3-Phenethylhexahydro-2H-oxazolo[3,2-i]indol-5(3H)-one,
8
(0.50 g, 1.75 mmol), was dissolved in a solution of 2 M HCl in absolute ethanol
(15 mL), and the mixture was stirred at room temperature for 20 h. After 20 h, the
reaction was quenched by addition of saturated sodium hydrogen carbonate and
extracted into ethyl acetate (3 ꢂ 40 mL). The combined organic fractions were dried
over anhydrous magnesium sulfate, and the solvent was removed under reduced press-
ure. The crude product was adsorbed onto silica gel and chromatographed using silica
gel as absorbent using a 2:1 mixture of ethyl acetate and light petroleum as eluent to
yield a colorless solid (0.40 g, 80%), a portion of which was recrystallized from dichlor-
omethane and hexanes to yield colorless crystals: mp 90–92 ꢁC (DCM=hexanes);
ꢀ1
;
1H
20
½aꢃD þ 52:0 (c 0.1, MeOH); IR (thin film, CH2Cl2) 3407, 2920, 1659 cm
NMR (CDCl3, 400 MHz) 1.02–1.12 (1 H, m), 1.23–1.38 (2 H, m), 1.83–1.86 (1 H,
m), 1.98–2.04 (1 H, m), 2.05–2.34 (4 H, m), 2.56–2.63 (1 H, m), 2.71–2.78 (2 H, m),
3.45–3.48 (1 H, m), 3.67 (1 H, dd, J 5.6, 11.2), 3.81–3.93 (2 H, m), 3.81 (1 H, d, J
7.7), 5.73 (1 H, s), 7.18–7.30 (5 H, m); 13C NMR (CDCl3, 100 MHz) 23.1, 27.1, 28.4,

PYRROLO[2,1-a]BENZAZEPINE
881
30.2, 32.6, 33.5, 56.1, 63.8, 64.6, 118.7, 126.0, 128.3 (2C), 128.5 (2C), 141.4, 162.7,
173.1; HRMS (FAB) 286 (MHþ, 100%). Calcd. for C18H24NO2: 286.1807 (MHþ);
found: 286.18097.
X-Ray Data for 10
C18H23NO2, M ¼ 285.37, orthorhombic, space group P212121, a ¼ 8.4089(7),
3
˚
˚
b ¼ 11.0955(9), c ¼ 16.2864(13) A, V ¼ 1519.5(2) A , T ¼ 150 K, Z ¼ 4, crystal dimen-
sions 0.37 ꢂ 0.05 ꢂ 0.03 mm3, silicon 111 monchromated synchrotron radiation
(k ¼ 0.6710 A), m ¼ 0.163 mmꢀ1; 12279 data measured using a Bruker APEX 2 CCD
˚
diffractometer, 2709 data were unique, Rint ¼ 0.088. All unique data were used in
refinement against F2 values to give final wR ¼ 0.1478 (on F2 for all data),
R ¼ 0.0544 [for 2463 data with F2 > 4r(F2)]; absolute structure could not be deter-
mined. Friedel pairs were merged. Programs used were Bruker APEX 2, SAINT,
SHELXTL,8 and local programs. Crystallographic data (excluding structure factors)
for the structure in this article has been deposited with the Cambridge Crystallo-
graphic Data Centre as supplementary publication number CCDC 773806. Copies
of the data can be obtained, free of charge, on application to CCDC, 12 Union Road,
Cambridge, CB2 1EZ, UK [Fax: þ44(0)-1223–336033 or e-mail: deposit@ccdc.ac.uk].
ACKNOWLEDGMENTS
The authors thank Loughborough University for facilities and the EPSRC
Eng. D. program and Charnwood Molecular Ltd. for support to J. M. R. Towler.
We also thank the STFC for synchrotron beam time at Daresbury Laboratory
and J. E. Warren and T. J. Prior for scientific support on Station 9.8.
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