A hydroformylation route to diazabicycloalkanes and oxazabicycloalkanes containing medium and large rings

Article abstract of DOI:10.1071/CH99097

Diazabicycloalkanes and oxazabicycloalkanes containing medium and large rings can be prepared by rhodium-catalysed reactions of N-alkenylpropane-1,3-diamines and 2-(alkenylamino)ethanols with H₂/CO in excellent yields without the need for high dilution. Selective ring opening of these compounds can lead to large heterocycles. CSIRO 1999.

Full text of DOI:10.1071/CH99097

C S I R O P U B L I S H I N G
Australian Journal
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Volume 52, 1999
© CSIRO Australia 1999
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Aust. J. Chem., 1999, 52, 1131–1138
A Hydroformylation Route to
Diazabicycloalkanes and Oxazabicycloalkanes
Containing Medium and Large Rings1
David J. Bergmann,A Eva M. Campi,A W. Roy JacksonA,B and
Antonio F. PattiA,C
A Department of Chemistry, Monash University, Clayton, Vic. 3800.
B Author to whom correspondence should be addressed
(email: W.R.Jackson@sci.monash.edu.au).
C School of Applied Sciences, Monash University, Vic. 3800.
Diazabicycloalkanes and oxazabicycloalkanes containing medium and large rings can be prepared by rhodium-
catalysed reactions of N-alkenylpropane-1,3-diamines and 2-(alkenylamino)ethanols with H2/CO in excellent
yields without the need for high dilution. Selective ring opening of these compounds can lead to large
heterocycles.
Introduction
Results and Discussion
Medium and large heterocycles are of interest in medici-
nal chemistry.2 We have previously attempted to synthesize
such compounds by hydroformylation reactions of some o-
alkenyloxybenzylamines.3 It was argued that an initially
formed amino aldehyde, still coordinated to the rhodium cat-
alyst, would cyclize without the need for high dilution con-
ditions. In the event, only polymeric material was obtained
and it was realized that the intermediate cyclic imines, if
formed, were prone to polymerization. This problem has
been surmounted4 by the use of secondary amines which
form more readily hydrogenated enamines or iminium salts5
Preparation of N-Alkenylpropane-1,3-diamines (1)–(3) and
2-(Alkenylamino)ethanols (4)–(6)
In general, the title compounds were prepared by reduc-
tive amination8 of the appropriate unsaturated aldehyde with
either propane-1,3-diamine or 2-aminoethanol and subse-
quent borohydride reduction or by reaction of the appropri-
ate unsaturated bromide or mesylate with a large excess of
propane-1,3-diamine or 2-aminoethanol (Scheme 1). N-
Benzyl-substituted diamines (7) and (8) were prepared by
reductive alkylation of the diamines (2) and (3) with
PhCHO/NaBH4.
6
and ligands such as BIPHEPHOS which promote hydrogena-
tion. An alternative method of preventing polymerization of
the initially formed unsaturated nitrogen heterocycle is to
react it with a suitable nucleophile. If this nucleophilic sub-
stitution is intramolecular then the formation of heterobi-
cyclic compounds (heterobicycles) eventuates. We have
established this methodology for the formation of 5,5 and
5,6-bicyclic systems7 and it appeared possible that the same
technique could be applied to the formation of larger ring
systems. Problems of chemoselectivity were encountered in
the preparation of 5,5 and 5,6 bicyclic systems due to
intramolecular carbonylation reactions (leading to lactams)
competing with hydroformylation. This problem was over-
come by the use of BIPHEPHOS as ligand.7 In addition, it
appears that intramolecular carbonylation is no longer a
problem when the formation of larger rings is involved.4
In this paper the application of the above methodology to
the synthesis of heterobicycles containing a medium or large
ring is described.
Manuscript received 6 August 1999
© CSIRO 1999
10.1071/CH99097
0004-9425/99/121131

1132
D. J. Bergmann et al.
products from these reactions appeared to be pure by 1H and
13C n.m.r. spectroscopy and detailed 2D-correlations were
used to establish the structures unambiguously. However,
analytically pure samples could not be obtained as distilla-
tion, chromatography (on a range of adsorbents) and isola-
tion as salts failed. The lability of the N–C–N bond in
aminals and of the corresponding N–C–O bond in hemi-
aminals is well known.10
Preparation of Heterobicycles Containing 13-Membered
Rings
Reaction of N-undec-10-enylpropane-1,3-diamine (1)
using BIPHEPHOS as ligand at 80° with H2/CO, 1 : 1 (initial
pressure 400 psi, 2.76 MPa), and a substrate/ligand/catalyst
ratio of 200 : 4 : 1 gave the diazabicycloheptadecane (9) in
80% yield (see Table, entry 1). The proposed reaction
sequence is shown in Scheme 2 though the cyclic iminium
ion could rearrange to the corresponding enamine which is
not shown.
Heterobicycles Containing 10-Membered Rings
Reaction of the ethanol derivative (4) gave the analogous
oxazabicyclohexadecane (10) again containing a 13-mem-
bered ring (entry 2). The high regioselectivity for products
arising from terminal hydroformylation, associated with the
use of BIPHEPHOS as ligand,6,7,9 was maintained. The initial
Reaction of N-oct-7-enylpropane-1,3-diamine (2) using
BIPHEPHOS as ligand gave the bicycle (11) in poor yield
(28%) even when the reaction temperature was reduced to
40° (entry 3). Areaction at 80° only gave polymeric material.
The difficulty of forming 10-membered carbocyclic rings is
well established but the ease of formation of heterocycles is
dependent on the pattern of heteroatom substitution.11
Reaction of the related secondary amine (7) using PPh3 as
ligand gave an excellent yield of bicyclic material, predomi-
nantly (12) but containing c. 10% of material originating
from branched chain aldehyde (entry 4). Reactions using
BIPHEPHOS as ligand at either 40 or 80° gave low yields of
cyclic product and significant amounts of hydrogenated
material, tentatively identified as hydrogenated starting
material and monocyclic material arising from hydrogena-
tion of the intermediate iminium species. Reaction using a
H2/CO gas ratio of 1:5 overcame the problem of this hydro-
genation12 and an excellent yield of (12) was obtained
(entry 5).
Table 1. Rhodium-catalysed reactions of N-alkenylpropane-1,3-diamines and N-alkenylaminoethanols with
H2/COA
Entry
Reactant
amine
Temp
(°C)
Ligand
Ratio
Bicyclo
product
Ring
sizes
YieldB
(%)
H2/CO
1
2
(1)
(4)
(2)
(7)
(7)
(5)
(5)
(3)
(8)
(8)
(6)
(6)
80
80
40
80
80
80
80
50
80
80
80
80
BIPHEPHOS
BIPHEPHOS
BIPHEPHOS
PPh3
1: 1
1: 1
1: 1
1: 1
1: 5
1: 1
1: 5
1: 1
1: 5
1: 1
1: 1
1: 5
(9)
(10)
(11)
(12)
(12)
(13)
(13)
(15)
(16)
(16)
(18)
(18)
6/13
5/13
6/10
6/10
6/10
5/10
5/10
6/8
80
80
3
28
4
95C
95
5
BIPHEPHOS
PPh3
6
93C
93
7
BIPHEPHOS
BIPHEPHOS
BIPHEPHOS
PPh3
8
74
9
6/8
95
10
11
12
6/8
14D
92C
92
PPh3
5/8
BIPHEPHOS
5/8
A Reaction conditions: substrate 0.5–1 mmol with substrate/[Rh(OAc)2]2/ligand 200: 1: 4 in benzene (5–10 ml) for 20 h
with an initial gas pressure, H2+CO, 2.76 MPa (400 psi).
B Isolated yields; products from reactions with BIPHEPHOS as ligand contained >95% of linear derived material.
C Containing c. 10% branch-chain derived product.
D The 6,7 bicyclo compound (17) arising from initial internal hydroformylation was the major product (38%).

1133
Diazabicycloalkanes and Oxazabicycloalkanes
The related alkenylaminoethanol (5) also gave excellent
yields (c. 93%) of the bicyclic compound (13) by using either
PPh3 and H2/CO, 1 : 1, or BIPHEPHOS and H2/CO, 1 : 5 (entries
6 and 7). The former reaction contained c. 10% of material
arising from branched chain aldehyde whereas the BIPHEPHOS
reaction was regiospecific. A reaction using BIPHEPHOS as
ligand with H2/CO, 1 : 1, at 40° again showed a preference
for hydrogenation leading to the monocyclic alcohol (14)
(75% yield).
Ring Opening Reactions
The selective cleavage of the bridging bond in some het-
erobicycles has been reported.13–15 Cleavage of the bridging
bond in the heterobicycles described in this paper to give
large ring compounds would further increase their useful-
ness. Selective ring opening reactions were thus attempted
with the bicyclic compound (9) containing a 13-membered
ring, the oxazabicyclononane (20) and the related (6,6) com-
pounds (22) and (23).
Heterocycles Containing Eight-Membered Rings
Reaction of N-hex-5-enylpropane-1,3-diamine (3) using
BIPHEPHOS as ligand with H2/CO, 1 : 1, at 80° gave polymeric
material but a reaction at 50° gave the diazabicyclododecane
(15) in good yield (74%, entry 8). Reaction of the N-benzyl
compound (8) with H2/CO, 1 : 1, and BIPHEPHOS as ligand at
either 40 or 80° gave a mixture of products but use of a
H2/CO, 1:5, gas mixture gave the bicyclic compound (16) in
excellent yield (95%, entry 9). A reaction using PPh3 as
ligand and H2/CO, 1 : 1, surprisingly gave a mixture of
bicyclic compounds in which the 6-methyl-1,8-diazabicy-
cloundecane (17) predominated (entry 10). This result was
obtained from repeat reactions and could be explained by
preferential chelation of a nitrogen atom in a seven- rather
than an eight-membered ring in the transition state leading to
the initial hydroformylation product.
Cleavage with DIBAL-H
Reactions of compound (9) with DIBAL-H under condi-
tions similar to those described by Yamamoto13 gave c. 60%
of 1,5-diazacycloheptadecane comparable with the yield of
cyclic amine obtained from 1,5-diazabicyclo[4.4.0]decane
(22) by ourselves and by Alder14 (Scheme 4).
Cleavage of the oxazabicyclononane (20) with DIBAL-H
was less successful leading to cleavage of the C–O bond and
formation of 3-(pyrrolidin-1-yl)propan-1-ol.
Cleavage with Cyanogen Bromide
Reaction of the aminoethanol (6) with PPh3 under these
conditions gave the oxazabicycloundecane (18) with only c.
10% branched material (entry 11). The major changes in
regioselectivity of the initial alkene hydroformylation that
occur on changing groups remote from the reaction site are
difficult to understand. Reaction using BIPHEPHOS and
H2/CO, 1 : 5, gave only (18) in high yield (entry 12). A reac-
tion using BIPHEPHOS but with a H2/CO gas ratio of 1 : 1 gave
a mixture from which monocyclic alcohols arising from
hydrogenation of the iminium intermediates were isolated.
Use of BrCN to cleave benzylic C–N bonds in annelated
tetrahydroisoquinoline derivatives has been extensively
developed as a route to medium ring heterocycles.16
Application of these reaction conditions (BrCN with MgO in
MeOH/CHCl3) to the bicyclic aminal (22) gave the 10-mem-
bered heterocycle (25) in excellent yield (84%) (Scheme 5).
Presumably the selectivity arises from stabilization of the
carbocation (26) by the adjacent nitrogen atom.
Reaction of 3-(Prop-2-enylamino)propan-1-ol (19)
A variation of the above trapping procedure was carried
out using the propenylaminopropanol (19). Reaction with
H2/CO, 1 : 1, using PPh3 as ligand gave a mixture of the oxaz-
abicyclononane (20) and the lactam (21) (Scheme 3). The
loss of chemoselectivity parallels that observed previously
when the possibility of forming five- or six-membered ring
lactams existed.7 The use of BIPHEPHOS as ligand appeared to
suppress lactam formation but other products were formed
and pure (20) was obtained in 33% yield.

1134
D. J. Bergmann et al.
2.76, t, 2H, J 6.9 Hz, H 1, 3, 1´; 4.89–5.04, m, 2H, H 11´; 5.81, ddt, 1H,
J 16.9, 10.1, 6.6 Hz, H10´. 13C n.m.r. ꢁ (50 MHz) 27.30, 28.83, 29.02,
29.35, 29.45, 29.97 (C 2´, 3´, 4´, 5´, 6´, 7´, 8´); 33.59, 33.71 (C 2´, 9´);
40.36 (C 3); 47.73 (C 1´); 50.06 (C 1); 114.02 (C 11´); 139.13 (C 10´).
Reaction of the related lactam (23) under the same condi-
tions led to formation of the nine-membered amino lactam
(27) in 47% yield (Scheme 6).
+
Mass spectrum (ESI ): m/z 226.9 (M+H)+.
N-(Oct-7-enyl)propane-1,3-diamine (2)
8-Bromooct-1-ene (1.50 g, 7.85 mmol) was added dropwise to
propane-1,3-diamine (5.82 g, 78.5 mmol) at 60° and the mixture was
stirred overnight at 60°. After cooling to ambient temperature, CH2Cl2
(100 ml) was added and washed with water (4×50ml). The organic layer
was dried (Na2SO4), filtered and concentrated to give N-(oct-7-
enyl)propane-1,3-diamine (2) as a clear oil (1.10 g, 76%) (Found: m/z
185.2014. (C11H24N2+H)+ requires m/z 185.2018). ꢀmax (neat) 3360s,
3077s, 2930s, 2854s, 1640m, 1574s, 1466s, 1318s, 1123m, 994m, 909s
cm–1. 1H n.m.r. ꢁ (200 MHz) 1.33–1.51, m, 8H, H2´, 3´, 4´, 5´; 1.64, p,
2H, J 7.0 Hz, H2; 1.86, br s, 3H, NH, NH2; 1.99–2.09, m, 2H, H6´;
2.58, t, 2H, J 7.4 Hz, 2.65, t, 2H, J 7.0 Hz, and 2.75, t, 2H, J 6.9 Hz, H1,
3, 1´; 4.89–5.04, m, 2H, H8´; 5.80, ddt, 1H, J 16.9, 10.1, 6.7 Hz, H7´.
13C n.m.r. ꢁ (50 MHz) 27.03, 28.63, 28.82, 29.82 (C 2´, 3´, 4´, 5´); 33.53
(C 2, 6´); 40.22 (C 3); 47.60 (C 1´); 49.91 (C1); 114.01 (C 8´); 138.85
However, in contrast, reaction of the oxazabicyclononane
(20) under these conditions gave a product whose n.m.r.
spectra suggested that the oxazanonane (28) and the
cyanamide (29) were both present. Only the cyanamide (29)
was isolated (26%) after chromatography on silica
(Scheme 7); it was presumed that the oxazanonane (28)
hydrolysed on the column.
+
(C 7´). Mass spectrum (ESI ): m/z 184.8 (M+H)+.
N-Benzyl-N´-(oct-7-enyl)propane-1,3-diamine (7)
Benzaldehyde (0.32 g, 2.99 mmol) in MeOH (2 ml) was added drop-
wise to a stirred solution of N-(oct-7-enyl)propane-1,3-diamine (2)
(0.50 g, 2.72 mmol) in MeOH (5 ml). The mixture was stirred for 3 h
before the addition of NaBH4 (0.15 g, 4.08 mmol). After a further 2 h,
conc. HCl was added cautiously to the mixture (pH 2), which was
diluted with water (30 ml), made basic (pH 11–12) by the addition of
NaOH pellets and extracted with ether (2×50 ml). The combined
organic extracts were washed with water (2×50 ml), dried (Na2SO4), fil-
tered and concentrated to give N-benzyl-N´-(oct-7-enyl)propane-1,3-
diamine (7) as a clear oil (0.56 g, 75%) (Found: m/z 275.2484.
(C18H30N2+H)+ requires m/z 275.2487). ꢀmax (neat) 3063m, 3028m,
2927s, 2854s, 1453s, 1122m, 909m, 734s, 698s cm–1. 1H n.m.r. ꢁ (200
MHz) 1.27–1.49, m, 8H, H 2´, 3´, 4´, 5´; 1.68, p, 2H, J 6.9 Hz, H2; 2.38,
br s, 2H, NH, NH; 2.54, t, 2H, J 7.0 Hz, 2.62, t, 2H, J 6.9 Hz, and 2.66,
t, 2H, J 6.9 Hz, H 1, 3, 1´; 3.75, s, 2H, PhCH2N; 4.89–5.04, m, 2H, H8´;
5.80, ddt, 1H, J 16.9, 10.1, 6.7 Hz, H 7´; 7.09–7.37, m, 5H, Ph. 13C
n.m.r. ꢁ (50 MHz) 27.16, 28.77, 28.96, 29.83, 29.92 (C 2´, 3´, 4´, 5´);
47.74, 48.33, 49.93 (C 1, 3, 1´); 53.92 (PhCH2N); 114.18 (C 8´);
126.90, 128.07, 128.35 (Ar CH); 139.03 (C 7´); 140.11 (C 1´´). Mass
Experimental
General conditions were as described previously.17 All n.m.r. spectra
were recorded for solutions in CDCl3 .unless otherwise stated.
Microanalyses were carried out by the Chemistry Department,
University of Otago, Dunedin, New Zealand. Attempts were made to
obtain analytically pure samples of the amino starting materials and
products by chromatography and/or distillation. Generally, combustion
analysis gave errors >±0.4% even though 1H and 13C n.m.r. spectra sug-
gested analytically pure material.
+
spectrum (ESI ): m/z 275.2 (M+H)+.
Materials
N-(Hex-5-enyl)propane-1,3-diamine (3)
BIPHEPHOS: 6,6Ј-{[3,3Ј-Bis(1,1-dimethylethyl)-5,5Ј-dimethoxy-1,1Ј-
biphenyl]-2,2Ј-diyl}bis(oxy)bis(dibenzo[d,f][1,3,2]dioxaphosphepin)
Hex-5-enyl mesylate (1.48 g, 8.31 mmol) was added dropwise to
stirred propane-1,3-diamine (6.16 g, 83.1 mmol) at 60° and the mixture
stirred overnight at 60°. The mixture was cooled to ambient tempera-
ture, CH2Cl2 (100 ml) was added and washed with water (4×50 ml). The
organic layer was dried (Na2SO4), filtered and concentrated to give N-
(hex-5-enyl)propane-1,3-diamine (3) as a clear oil (0.89 g, 69%), b.p.
(oven) 90–95°/12 mm (Found: m/z 157.1701. (C9H20N2+H)+ requires
m/z 157.1705). ꢀmax (neat) 3286s(br), 3076m, 2929s, 2856s, 1640m,
1458m, 1126m, 994m, 909s cm–1. 1H n.m.r. ꢁ (400 MHz) 1.21, br s, 3H,
NH, NH2; 1.28–1.35, m, 2H, H 3´; 1.37–1.44, m, 2H, H 2´; 1.49–1.57,
m, 2H, H 2; 1.94–1.99, m, 2H, H4´; 2.50, t, 2H, J 7.0 Hz, H3; 2.57, t,
2H, J 7.0 Hz, H1´; 2.66, t, 2H, J 6.8 Hz, H1; 4.82–4.93, m, 2H, H 6´;
5.65–5.75, m, 1H, H5´. 13C n.m.r. ꢁ (100 MHz) 26.55 (C 3´); 29.49
(C 2´); 33.50, 33.77 (C 2, 4´); 40.45 (C 3); 47.79 (C 1´); 49.83 (C 1);
BIPHEPHOS was prepared according to a literature procedure.6
N-(Undec-10-enyl)propane-1,3-diamine (1)
Undec-10-enal18 (1.00 g, 5.94 mmol) in MeOH (5 ml) was added
dropwise to a solution of propane-1,3-diamine (2.20 g, 29.7 mmol) in
MeOH (10 ml) and the mixture allowed to stir at ambient temperature
for 2 days. The reaction mixture was cooled to 0° and NaBH4 (0.45 g,
11.9 mmol) was added portionwise. The mixture was allowed to warm
to ambient temperature, stirred for a further 2 h, again cooled to 0°, fol-
lowed by the addition of conc. HCl (to pH 2). The mixture was diluted
with water (30 ml), made basic (pH 11–12) by the addition of NaOH
pellets and extracted with ether (2×50 ml). The combined organic
extracts were washed with water (2×50 ml), dried (Na2SO4), filtered
and concentrated to give N-(undec-10-enyl)propane-1,3-diamine (1) as
a clear oil (0.83 g, 62%). Kugelrohr distillation b.p.(oven) 90°/0.1 mm
(Found: m/z 227.2477. (C14H30N2+H)+ requires m/z 227.2487). ꢀmax
(neat) 3332s, 3261s, 3073s, 2916s, 2876s, 2853s, 2812s, 2774m,
1639m, 1482m, 1471s, 1374m, 1134m, 1056m, 992m, 913s, 720m,
675m, 637m cm–1. 1H n.m.r. ꢁ (200 MHz) 1.28–1.51, m, 14H, H 2´, 3´,
4´, 5´, 6´, 7´, 8´; 1.64, p, 2H, J 7.0 Hz, H2; 1.90, br s, 3H, NH2, NH;
1.99–2.08, m, 2H, H9´; 2.58, t, 2H, J 7.4 Hz, 2.66, t, 2H, J 7.0 Hz, and
114.30 (C 6´); 138.61 (C 5´). Mass spectrum (ESI ): m/z 156.7 (M+H)+.
+
N-Benzyl-N´-(hex-5-enyl)propane-1,3-diamine (8)
Benzaldehyde (0.61 g, 5.71 mmol) in MeOH (2 ml) was added drop-
wise to a stirred solution of N-(hex-5-enyl)propane-1,3-diamine (3)
(0.89 g, 5.71 mmol) in MeOH (5 ml) and the mixture stirred for 3 h.
NaBH4 (0.32 g, 8.56 mmol) was added and stirring continued for 2 h.
Conc. HCl was added cautiously to the mixture (pH 2), which was
diluted with water (30 ml), made basic (pH 11–12) with NaOH pellets,

1135
Diazabicycloalkanes and Oxazabicycloalkanes
110°/20 mm (Found: m/z 144.1383. (C8H17NO+H)+ requires m/z
144.1388). ꢀmax (neat) 3299s(br), 3077s, 2929s, 2857s, 1641m, 1456s,
1122m, 1062s, 994m, 910s cm–1. 1H n.m.r. ꢁ (400 MHz) 1.31–1.39, m,
2H, H 3´; 1.41–1.48, m, 2H, H 2´; 2.00 (apparent q), 2H, J 7.1 Hz, H4´;
2.55, t, 2H, J 7.1 Hz, H1´; 2.67, t, 2H, J 5.2 Hz, H2; 2.84, br s, 1H, NH
or OH; 3.58, t, 2H, J 5.2 Hz, H 1; 4.63, br s, 1H, OH or NH; 4.88, ddt,
1H, J 10.2, 2.4, 1.2 Hz, H6´E; 4.93, ddt, 1H, J 17.1, 3.2, 1.6 Hz, H 6´Z;
5.73, ddt, 1H, J 16.9, 10.2, 6.7 Hz, H 5´. 13C n.m.r. ꢁ (100 MHz) 26.49
(C 3´); 29.34 (C 2´); 33.49 (C 4´); 49.39 (C 1´); 51.26 (C 2); 60.64 (C 1);
and extracted with CH2Cl2 (2×50 ml). The combined organic extracts
were washed with water (2×50 ml), dried (Na2SO4), filtered and con-
centrated to give a cloudy oil (1.66 g). Kugelrohr distillation gave N-
benzyl-N´-(hex-5-enyl)propane-1,3-diamine (8) as a clear oil (0.95 g,
68%), b.p.(oven) 150°/0.5 mm (Found: C, 77.7; H, 10.6; N, 11.2.
C16H26N2 requires C, 78.0; H, 10.6; N, 11.4%.) ꢀmax (neat) 3290m(br),
3063m, 3027m, 2928s, 2855s, 2813s, 1640m, 1494m, 1454s, 1126s,
994m, 910s, 734s, 698s cm–1. 1H n.m.r. ꢁ (400 MHz) 1.37–1.44, m, 2H,
H3´; 1.46–1.53, m, 2H, H 2´; 1.61, br s, 2H, NH, NH; 1.70, p, 2H, J 6.8
Hz, H 2; 2.06, q, 2H, J 7.1 Hz, H4´; 2.59, t, 2H, J 7.0 Hz, H1´; 2.67, t,
2H, J 7.2 Hz, and 2.69, t, 2H, J 7.4 Hz, H 1, 3; 3.78, s, 2H, PhCH2N;
4.91–4.96, m, 1H, H 6´E; 5.00, dq, 1H, J 17.1, 1.6 Hz, H 6´Z; 5.80, ddt,
1H, J 16.9, 10.2, 6.7 Hz, H 5´; 7.22–7.33, m, 5H, Ph. 13C n.m.r. ꢁ (100
MHz) 26.62 (C 3´); 29.52 (C 2´); 30.18 (C 2); 33.62 (C 4´); 47.94 (C 1´);
48.55 (C 3); 49.89 (C 1); 54.03 (PhCH2N); 114.44 (C 6´); 126.84,
128.04, 128.34 (Ar CH); 138.74 (C 5´); 140.39 (C 1´´). Mass spectrum
+
114.47 (C 6´); 138.55 (C 5´). Mass spectrum (ESI ): m/z 143.6 (M+H)+.
3-(Prop-2-enylamino)propanol (19)19
A sample of the alcohol (19) was prepared by addition of allylamine
to ethyl acrylate followed by LiAlH4 reduction of the resulting ester20
(80%). ꢀmax (neat) 3288s(br), 2934s, 1458m, 1109m, 1069s, 996m cm–1.
1H n.m.r. ꢁ (400 MHz) 1.71, m, 2H, H2; 2.82, t, 2H, J 6.1 Hz, H3; 3.24,
dt, 2H, J 6.0, 1.4 Hz, H1´; 3.75, t, 2H, J 5.6 Hz, H1; 5.10, ddt (appar-
ent dq), 1H, J 10.3, 1.3, 1.3 Hz, H3´E; 5.17, ddt (apparent dq), 1H, J
17.2, 1.6, 1.6 Hz, H3´Z; 5.88, ddt, 1H, J 17.2, 10.3, 6.0 Hz, H2´. 13C
n.m.r. ꢁ (100 MHz) 31.11 (C 2); 48.17 (C 3); 52.07 (C 1´); 62.89 (C 1);
116.13 (C 3´); 136.10 (C 2´). Mass spectrum (EI): m/z 114 (M+, 4%), 98
(3), 84 (10), 70 (100), 56 (25).
+
(ESI ): m/z 246.9 (M+H)+.
2-(Undec-10-enylamino)ethanol (4)
Undec-10-enal (1.00 g, 5.94 mmol) in MeOH (5 ml) was added
dropwise to a solution of 2-aminoethanol (0.36 g, 5.94 mmol) in MeOH
(10 ml) and the mixture allowed to stir at ambient temperature for 1 h.
The mixture was cooled to 0° and NaBH4 (0.45 g, 11.9 mmol) was
added portionwise. The reaction mixture was allowed to warm to
ambient temperature, stirred for a further 2 h, again cooled to 0°, fol-
lowed by the addition of conc. HCl (to pH 2). The mixture was diluted
with water (30 ml), made basic (pH 11–12) by the addition of NaOH
pellets and extracted with ether (2×50 ml). The combined organic
extracts were washed with water (2×50 ml), dried (Na2SO4), filtered
and concentrated to give 2-(undec-10-enylamino)ethanol (4) as a clear
oil (0.45 g, 36%). b.p.(oven) 110°/0.2 mm (Found: m/z 214.2165.
(C13H27NO+H)+ requires m/z 214.2171). ꢀmax (neat) 3271s, 3075s,
2917s, 2853s, 1642m, 1463s, 1438m, 1128m, 1077s, 994m, 955m,
936m, 917m, 862m cm–1. 1H n.m.r. ꢁ (400 MHz) 1.28, br s, 10H, and
1.36–1.39, m, 2H, H 3´, 4´, 5´, 6´, 7´, 8´; 1.49, p, 2H, J 7.0 Hz, H 2´;
2.04, m, 2H, H9´; 2.40, br s, 1H, OH; 2.61, t, 2H, J 7.2 Hz, H 1´; 2.77,
t, 2H, J 5.2 Hz, H 2; 3.64, t, 2H, J 5.2 Hz, H 1; 4.93, dq, 1H, J 10.2, 1.1
Hz, H11´E; 4.99, dq, 1H, J 17.1, 2.1 Hz, H 11´Z; 5.81, ddt, 1H, J 16.9,
10.2, 6.7 Hz, H 10´. 13C n.m.r. ꢁ (100 MHz) 27.29, 28.94, 29.12, 29.44,
29.53, 29.54, 30.06 (C 2´, 3´, 4´, 5´, 6´, 7´, 8´); 33.79 (C 9´); 49.55
(C 1´); 51.15 (C 2); 60.79 (C 1); 114.10 (C 11´); 139.20 (C 10´). Mass
Reactions with H2/CO
General Conditions
Reactions were carried out in a 100 ml Parr autoclave with a glass
sleeve containing a stirrer bead. The substrate (0.1–0.3 g, c. 1 mmol),
the rhodium catalyst precursor, and the ligand (in ratio 200 : 1: 4) were
placed in the autoclave under N2 followed by deoxygenated benzene
(10 ml).
The vessel was flushed, and evacuated, three times with 200 psi
(1.38 MPa) of H2/CO (1: 1 molar mixture) and then pressurized to
400 psi (2.76 MPa). Alternatively it was flushed with H2, and then pres-
surized to an initial pressure of 400 psi (2.76 MPa) with an H2/CO (1 : 5)
gas mixture. The reaction was kept at the reported temperature for 20 h,
the autoclave cooled, the gases were released and the contents analysed
as reported. In general, ratios of products including regioisomers were
determined by relative peak areas of appropriate hydrogens in 1H n.m.r.
spectra and/or relative signal intensities of comparable carbons in 13C
n.m.r. spectra. Selective extraction of the total product with light
petroleum gave in most cases n.m.r. pure material in higher yields than
chromatography on silica or alumina.
+
spectrum (ESI ): m/z 213.9 (M+H)+.
Reactions involving the use of [Rh(OAc)2]2 and PPh3 as the catalyst
system at 80° for 20 h are referred to as ‘the usual conditions’.
Reactions leading to cyclized products were repeated at least once
and gave product ratios within ±5% reproducibility.
2-(Oct-7-enylamino)ethanol (5)
8-Bromooct-1-ene (1.00 g, 5.23 mmol) was added dropwise to
stirred 2-aminoethanol (1.60 g, 26.2 mmol) at 60° and the mixture
stirred overnight at 60°. The mixture was cooled to ambient tempera-
ture, CH2Cl2 (100 ml) was added and washed with water (4×50 ml). The
organic layer was dried (Na2SO4), filtered and concentrated to give 2-
(oct-7-enylamino)ethanol (5) as a clear oil (0.84 g, 94%) (Found: m/z
172.1693. (C10H21NO+H)+ requires m/z 172.1701). ꢀmax (neat)
3302s(br), 3076s, 2926s, 2855s, 1641m, 1459s, 1122m, 1062s, 995m,
1,14-Diazabicyclo[11.4.0]heptadecane (9)
N-(Undec-10-enyl)propane-1,3-diamine (1) (0.20 g, 0.89 mmol),
BIPHEPHOS (13.9 mg, 17.6 ꢂmol) and rhodium(II) acetate dimer (2.0 mg,
4.4 ꢂmol) were reacted under the standard conditions with
H2/CO (1: 1). Concentration of the solvent gave 1,14-diazabicy-
clo[11.4.0]heptadecane (9) as a yellow viscous oil (0.19 g, 80%)
(Found: m/z 239.2480. (C15H30N2+H)+ requires m/z 239.2487). ꢀmax
(neat) 3285m, 2922s, 2852s, 1464s, 1368m, 1250m, 1182m, 1128m,
1096m, 900m, 734s cm–1. 1H n.m.r. ꢁ (400 MHz) 1.20, m, 12H, H5, 6,
7, 8, 9, 10; 1.25–1.37, m, 7H, H 3, 4, 11, 16A; 1.53–1.60, m, 3H, H16B,
12; 2.17–2.24, m, 1H, H2A; 2.34, dt, 1H, J 9.1, 2.4 Hz, H17A;
2.48–2.53, m, 1H, H 2B; 2.58, t, 1H, J 11.0 Hz, H15A; 2.97, m, 1H,
H17B; 3.00, m, 1H, H 15B; 3.07–3.09, m, 1H, H13. 13C n.m.r. ꢁ (100
MHz) 25.02 (C 11); 25.76, 26.50, 27.53, 29.40, 29.42, 29.76 (C 3, 4, 5,
6, 7, 8, 9, 10, 16); 32.91 (C 12); 44.90 (C 15); 51.13, 51.16 (C 2, 17);
1
909s cm–1. H n.m.r. ꢁ (200 MHz) 1.33–1.52, m, 8H, H 2´, 3´, 4´, 5´;
1.99–2.09, m, 2H, H 6´; 2.06, t, 2H, J 7.4 Hz, H 1´; 2.73, t, 2H, J 5.2 Hz,
H2; 3.06, br s, 2H, NH, OH; 3.65, t, 2H, J 5.3 Hz, H 1; 4.89–5.05, m,
2H, H8´; 5.08, ddt, 1H, J 16.9, 10.1, 6.7 Hz, H7´. 13C n.m.r. ꢁ (50 MHz)
27.09, 28.76, 28.92, 29.84 (C 2´, 3´, 4´, 5´); 33.64 (C 6´); 49.59 (C 1´);
51.28 (C 2); 60.60 (C 1); 114.18 (C 8´); 138.94 (C 7´). Mass spectrum
+
(ESI ): m/z 172.0 ((M+H)+.
2-(Hex-5-enylamino)ethanol (6)
Hex-5-enyl mesylate (1.0 g, 5.62 mmol) was added dropwise to
stirred 2-aminoethanol (3.43 g, 56.2 mmol) at 60° and the mixture
stirred overnight before being cooled to ambient temperature. CH2Cl2
(100 ml) was added and the solution washed with water (4×50 ml). The
organic layer was dried (Na2SO4), filtered and concentrated to give 2-
(hex-5-enylamino)ethanol (6) as a clear oil (0.44 g, 55%), b.p.(oven)
+
75.99 (C 13). Mass spectrum (ESI ): m/z 239.0 (M+H)+.
Dry HCl(g) was bubbled through a solution of 1,14-diaza-
bicyclo[11.4.0]heptadecane (9) (0.05 g) in CHCl3 (10 ml) for 1 h.
Evaporation of the solvent gave a highly viscous oil. 1H and 13C n.m.r.
spectroscopy indicated a complex mixture of products (0.06 g).

1136
D. J. Bergmann et al.
14-Oxa-1-azabicyclo[11.3.0]hexadecane (10)
11-Oxa-1-azabicyclo[8.3.0]tridecane (13)
2-(Undec-10-enylamino)ethanol (4) (0.10 g, 0.47 mmol), BIPHEPHOS
(7.3 mg, 9.4 ꢂmol) and rhodium(II) acetate dimer (1.0 mg, 2.4 ꢂmol)
were reacted under the standard conditions with H2/CO (1 : 1).
Concentration of the solvent gave 14-oxa-1-azabicyclo[11.3.0]hexade-
cane (10) as a yellow viscous oil (0.10 g, 80%) (Found: m/z 226.2166.
(C14H27NO+H)+ requires m/z 226.2171). ꢀmax (neat) 2925s, 2853s,
2-(Oct-7-enylamino)ethanol (5) (0.20 g, 1.17 mmol), PPh3 (6.1 mg,
23.4 ꢂmol) and rhodium(II) acetate dimer (2.6 mg, 5.8 ꢂmol) were
reacted under the standard conditions with H2/CO (1: 1). Concentration
of the solvent gave 11-oxa-1-azabicyclo[8.3.0]tridecane (13) as a
yellow oil (0.20 g, 93%) (Found: m/z 184.1696. (C11H23NO+H)+
requires m/z 184.1701). ꢀmax (neat) 2926s, 2853s, 1731m, 1651m,
1464s, 1368m, 1157s, 1120s, 1071s, 920m, 726s cm–1. 1H n.m.r. ꢁ (400
MHz) 1.22–1.38, m, 8H, H4, 5, 6, 7; 1.42–1.59, m, 6H, H3, 8, 9; 2.21,
dt, 1H, J 11.6, 7.1 Hz, H2A; 2.43–2.55, m, 1H, H13A; 2.56–2.62, m,
1H, H 2B; 3.22, ddd, 1H, J 10.0, 6.1, 4.8 Hz, H 13B; 3.76–3.88, m, 2H,
H12; 3.95, dd, 1H, J 6.4, 3.3 Hz, H 10. 13C n.m.r. ꢁ (100 MHz) 25.00
(C 8); 27.36 (C 3); 29.06, 29.37, 29.49, 29.62 (C 4, 5, 6, 7); 34.04 (C 9);
52.21 (C 13); 53.09 (C 2); 64.14 (C 12); 96.61 (C 10). Mass spectrum
1
1466m, 1182m, 1060m cm–1. H n.m.r. ꢁ (400 MHz) 1.20, br s, 14H,
H4, 5, 6, 7, 8, 9, 10; 1.33–1.50, m, 6H, H 3, 11, 12; 2.13–2.20, m, 1H,
H2A; 2.39–2.46, m, 1H, H 16A; 2.48–2.55, m, 1H, H 2B; 3.15, (apparent
p), 1H, J 6.1 Hz, H16B; 3.74–3.78, m, 2H, H 15; 3.90, dd, 1H, J 6.1, 3.6
Hz, H 13. 13C n.m.r. ꢁ (100MHz) 25.03 (C 11); 27.40 (C 3); 29.12,
29.48, 29.52, 29.55, 29.70 (C 4, 5, 6, 7, 8, 9, 10); 34.11 (C 12); 52.13
+
(C 16); 53.28 (C 2); 64.15 (C 15); 96.71 (C 13). Mass spectrum (ESI ):
m/z 226.9 (M+H)+.
(ESI ): m/z 183.6 (M+H)+. N.m.r. spectroscopy indicated less than 10%
+
of the internal product, 8-methyl-10-oxa-1-azabicyclo[7.3.0]dodecane.
1H n.m.r. ꢁ (400 MHz) 1.08, d, J 7.0 Hz, CH3. 13C n.m.r. ꢁ (100 MHz)
13.05 (CH3); 46.16 (C 8); 95.95 (C 9).
1,11-Diazabicyclo[8.4.0]tetradecane (11)
N-(Oct-7-enyl)propane-1,3-diamine (2) (0.10 g, 0.54 mmol),
BIPHEPHOS (8.5 mg, 10.9 ꢂmol) and rhodium(II) acetate dimer (1.2 mg,
2.7 ꢂmol) were reacted under the standard conditions with H2/CO
(1: 1) at 40° for 44 h. A significant amount of benzene-insoluble
polymer lined the autoclave glass sleeve. Concentration of the benzene-
soluble fraction gave 1,11-diazabicyclo[8.4.0]tetradecane (11) as a
yellow oil (0.03 g, 28%) (Found: m/z 197.2008. (C12H24N2+H)+
requires m/z 197.2018). ꢀmax (neat) 3288m(br), 2926s, 2854s, 1638s,
1462s, 1369m, 1306m, 1250m, 1173m, 1064m, 731s cm–1. 1H n.m.r. ꢁ
(400 MHz) 1.28, m, 8H, H 4, 5, 6, 7; 1.44, m, 5H, H3, 8, 13A;
1.56–1.67, m, 3H, H9, 13B; 2.29, m, 1H, H 2A; 2.41, t, 1H, J 10.4 Hz,
H14A; 2.56, m, 1H, H2B; 2.65, t, 1H, J 11.1 Hz, H 12A; 3.04, m, 1H,
H14B; 3.07, m, 1H, H 12B; 3.14, m, 1H, H 10. 13C n.m.r. ꢁ (100 MHz)
25.26 (C 3); 25.87 (C 9); 27.01 (C 4); 29.24, 29.42, 29.52, 29.83 (C 5, 6,
7, 8); 33.10 (C 13); 45.03 (C 12); 51.28 (C 2); 51.61 (C 14); 76.11
Column chromatography (basic alumina: 1% MeOH/CH2Cl2)
resulted in product decompostion with 11-oxa-1-azabicyclo-
[8.3.0]tridecane (13) being recovered in low yield (0.03 g, 28%) and
without any improvement in the purity.
A reaction of (5) (0.10 g, 0.59 mmol), BIPHEPHOS (9.2 mg, 11.7
ꢂmol) and rhodium(II) acetate dimer (1.3 mg, 2.9 ꢂmol) with H2/CO
(1: 1) at 80° gave a reasonably pure sample of the tridecane (13) (0.10
g, 93%).
A reaction of (5) under the above conditions but with H2/CO (1: 1)
at 40° for 44 h gave 2-(decahydroazecin-1-yl)ethanol (14) as a yellow
oil (0.08 g, 75%) (Found: m/z 186.1856. (C11H23NO+H)+ requires m/z
186.1858). ꢀmax (neat) 3385s(br), 2926s, 2854s, 1465s, 1368m, 1172m,
1053s, 732m cm–1. 1H n.m.r. ꢁ (400 MHz) 1.43–1.57, m, 14H, H3´, 4´,
5´, 6´, 7´, 8´, 9´; 2.44, t, 4H, J 7.3 Hz, H2´, 10´; 2.57, t, 2H, J 5.1 Hz,
H2; 3.53, t, 2H, J 4.9 Hz, H 1. 13C n.m.r. ꢁ (100 MHz) 26.90, 27.31,
29.69, 29.76 (C 3´, 4´, 5´, 6´, 7´, 8´, 9´); 53.80 (C 2´, 10´); 55.45 (C 2);
+
(C 10). Mass spectrum (ESI ): m/z 196.9 ((M+H)+, 54%), 393.1
((2M+H)+, 100).
+
58.32 (C 1). Mass spectrum (ESI ): m/z 186.0 ((M+H)+, 16%), 371.3
11-Benzyl-1,11-diazabicyclo[8.4.0]tetradecane (12)
((2M+H)+, 100).
The diamine (7) (0.10 g, 0.37 mmol), PPh3 (1.9 mg, 7.3 ꢂmmol) and
rhodium(II) acetate dimer (0.8 mg, 1.8 ꢂmol) were reacted under the
standard conditions with H2/CO (1: 1). Concentration of the solvent
gave 11-benzyl-1,11-diazabicyclo[8.4.0]tetradecane (12) as a yellow
oil (0.10 g, 95%) (Found: m/z 287.2486. (C19H30N2+H)+ requires m/z
287.2487). ꢀmax (neat) 3062m, 3027m, 2929s, 2853s, 2805s, 1494m,
1,9-Diazabicyclo[6.4.0]dodecane (15)
N-(Hex-5-enyl)propane-1,3-diamine (3) (0.10 g, 0.64 mmol),
BIPHEPHOS (10.0 mg, 12.8 ꢂmol) and rhodium(II) acetate dimer (1.4 mg,
3.2 ꢂmol) were reacted with H2/CO (1: 1) at 50° for 44 h.
Concentration of the solvent gave 1,9-diazabicyclo[6.4.0]dodecane
1
1453s, 1356m, 1117m, 1071m, 1027m, 733s, 698s cm–1. H n.m.r. ꢁ
(15) as
a yellow oil (0.80 g, 74%) (Found: m/z 169.1700.
(C10H20N2+H)+ requires m/z 169.1705). ꢀmax (neat) 3286m(br), 2931s,
2857s, 1640s, 1459s, 1376m, 1074m, 910s, 754s, 732s cm–1. 1H n.m.r.
ꢁ (200 MHz) 1.20–1.50, m, 9H, H3, 4, 5, 6, 11A; 1.59–1.75, m, 3H,
H11B,7; 2.14–2.42, m, 2H, H2A, 12A; 2.48–2.71, m, 2H, H 2B, 10A;
3.03, m, 1H, H12B; 3.09, m, 1H, H10B; 3.16, m, 1H, H8. 13C n.m.r. ꢁ
(50 MHz) 25.20, 25.78, 26.53, 27.67, 29.89 (C 3, 4, 5, 6, 11); 32.99
(400 MHz) 1.31–1.45, m, 13H, H3, 4, 5, 6, 7, 8, 13A; 1.47–1.59, m, 1H,
H9A; 1.60–1.71, m, 1H, H 9B; 1.82–1.98, m, 1H, H 13B; 2.39–2.45, m,
1H, H 2A; 2.52–2.56, m, 1H, H 2B; 2.60–2.62, m, 2H, H 12A, 14A;
2.79–2.87, m, H 12B, 14B; 3.31, m, 1H, H10; 3.71, d, 1H, J 13.5 Hz,
PhCHAN; 3.80, d, 1H, J 13.6 Hz, PhCHBN; 7.19–7.22, m, 1H, and
7.25–7.35, m, 4H, ArH. 13C n.m.r. ꢁ (100 MHz) 20.37 (C 13); 22.90
(C 9); 26.60 (C 8); 27.55, 28.00 (C 3, 4); 29.67, 29.71, 29.79 (C 5, 6, 7);
45.14 (C 12); 46.18 (C 14); 52.94 (C 2); 56.76 (PhCH2N); 76.56 (C 10);
126.56 (C 4´); 128.02, 128.29 (C 2´, 3´, 5´, 6´); 140.59 (C 1´). Mass
+
(C 7); 44.96 (C 10); 51.19 (C 2, 12); 75.96 (C 8). Mass spectrum (ESI ):
m/z 168.8 (M+H)+.
9-Benzyl-1,9-diazabicyclo[6.4.0]dodecane (16) and 8-Benzyl-6-
methyl-1,8-diazabicyclo[5.4.0]undecane (17)
+
spectrum (ESI ): m/z 287.1 ((M+H)+, 60%); 573.5 ((2M+Na)+, 100).
N.m.r. spectroscopy indicated less than 10% of the internal product, 10-
benzyl-8-methyl-1,10-diazabicyclo[7.4.0]tridecane. 1H n.m.r. ꢁ (400
MHz) 1.07, d, J 7.0 Hz, CH3. 13C n.m.r. ꢁ (100 MHz) 13.25 (CH3);
55.70 (C 8); 75.18 (C 9).
The diamine (8) (0.20 g, 0.81 mmol), PPh3 (4.3 mg, 16.3 ꢂmol) and
rhodium(II) acetate dimer (1.8 mg, 4.1 ꢂmol) were reacted under the
standard conditions with H2/CO (1: 1). Concentration of the solvent
gave a yellow oil (0.24 g). The crude 1H and 13C n.m.r. spectra of the
total product indicated a 30: 70 mixture of linear to branched products.
Column chromatography (alumina: 20% EtOAc/light petroleum) gave
8-benzyl-6-methyl-1,8-diazabicyclo[5.4.0]undecane (17) as a clear oil
(0.08 g, 38%) (Found: m/z 259.2175. (C17H26N2+H)+ requires m/z
259.2174). ꢀmax (neat) 3026m, 2926s, 2853s, 1494m, 1453s, 1363m,
1148m, 1115s, 1045w, 1027m, 737s, 698s cm–1. 1H n.m.r. ꢁ (400 MHz)
0.96, d, 3H, J 6.7 Hz, CH3; 1.37–1.44, m, 1H, H5A; 1.46–1.52, m, 3H,
H3A, 4A, 10A; 1.57–1.62, m, 2H, H5B, 3B; 1.63–1.70, m, 2H, H4B, 10B;
2.17, m, 1H, H6; 2.52–2.58, m, 1H, H9A; 2.63, t, 1H, J 13.2 Hz, H2A;
2.70, p, 1H, J 5.8 Hz, H11A; 2.94–3.08, m, 4H, H2B, 7, 9B, 11B; 3.77,
d, 1H, J 13.7 Hz, and 4.01, d, 1H, J 13.7 Hz, PhCH2N; 7.20, t, 1H, J 7.2
Column chromatography (basic alumina) resulted in product
decomposition giving still impure bicyclic amine (12) in poor yield
(0.04 g, 38%).
A reaction of the diamine (7) (0.10 g, 0.37 mmol), BIPHEPHOS (5.7
mg, 7.3 ꢂmol) and rhodium(II) acetate dimer (0.8 mg, 1.8 ꢂmol) with
H2/CO (1 : 5) gave the bicyclic compound (12) as a yellow oil (0.10 g,
95%).
Reactions of (7) using BIPHEPHOS as ligand and H2/CO (1: 1) for 40
h at 40° or 20 h at 80° gave a mixture of products. Mass spectroscopy
+
(ESI ) suggested the presence of starting material (7) (m/z 275.2), hydro-
genated starting material (m/z 277.1) and hydrogenated intermediate
iminium cation (m/z 289.1).

1137
Diazabicycloalkanes and Oxazabicycloalkanes
(lit.21 60–61°/14 mm), gave 5-oxa-1-azabicyclo[4.3.0]nonane (20) as a
clear oil (0.11 g, 33%). ꢀmax (neat) 2930s, 2852s, 2796m, 1652s, 1453m,
1340m, 1158m, 1065m cm–1. 1H n.m.r. ꢁ (400 MHz) 1.06, m, 1H, H3A;
1.60–1.69, m, 1H, H 7A; 1.69–1.77, m, 1H, H 8A; 1.83–1.90, m, 1H,
H8B; 1.91–1.96, m, 1H, H7B; 1.97–2.05, m, 1H, H3B; 2.66, dt, 1H, J
8.5, 3.6 Hz, H 9A; 3.02–3.09, m, 3H, H9B, 2; 3.59, dq, 1H, J 11.4, 2.4
Hz, H4´; 7.28, t, 2H, J 7.2 Hz, H 3´,5´; 7.36, d, 2H, J 7.4 Hz, H 2´,6´.
13C n.m.r. ꢁ (100 MHz) 18.66 (C 10); 21.11 (CH3); 25.23 (C 3); 26.98
(C 4); 33.33 (C 5); 35.08 (C 6); 46.33 (C 9); 50.39 (C 11); 53.48 (C 2);
55.09 (PhCH2N); 85.59 (C 7); 126.52 (C 4´); 128.07 (C 3´, 5´); 128.75
+
(C 2´, 6´); 141.02 (C 1´). Mass spectrum (ESI ): m/z 259.0 (M+H)+.
Further elution (20–50% EtOAc/light petroleum) gave an impure
sample of 9-benzyl-1,9-diazabicyclo[6.4.0]dodecane (16) (0.03 g,
14%) (Found: m/z 259.2173. C17H26N2 requires m/z 259.2174). ꢀmax
Hz, H 4A; 3.94–3.98, m, 1H, H 4B; 4.37, dd, 1H, J 5.1, 1.8 Hz, H 6. 13
C
n.m.r. ꢁ (100 MHz) 20.12 (C 3); 21.15 (C 8); 31.68 (C 7); 45.73 (C 2);
1
(neat) 2930s, 2854m, 1453m, 1356m, 734m, 698s cm–1. H n.m.r. ꢁ
+
47.57 (C 9); 67.06 (C 4); 91.55 (C 6). Mass spectrum (ESI ): m/z 127.4
(M+H)+.
(200 MHz) 1.06–1.51, m, 9H, H 3, 4, 5, 6, 11A; 1.58–1.66, m, 2H, H 7;
1.80–2.11, m, 1H, H 11B; 2.19–2.35, m, 1H, H 2A; 2.49–2.51, m, 1H,
H2B; 2.60–2.75, m, 2H, H 10A, 12A; 2.82–2.94, m, 2H, H10B, 12B;
3.26–3.40, m, 1H, H8; 3.71–3.84, m, 2H, PhCH2N; 7.20–7.42, m, 5H,
ArH. 13C n.m.r. ꢁ (100 MHz) 20.31, 22.68, 26.57, 27.55, 27.97, 29.32
(C 3, 4, 5, 6, 7, 11); 45.03 (C 10); 46.06 (C 12); 52.91 (C 2); 56.74
(PhCH2N); 76.45 (C 8); 126.53, 127.98, 128.55 (Ar CH); 140.51 (C 1´).
A reaction of (19) (0.30 g, 2.61 mmol), PPh3 (13.7 mg, 52.2 ꢂmol)
and rhodium(II) acetate dimer (5.8 mg, 13.0 ꢂmol) with H2/CO (1: 1)
gave a yellow oil (0.31 g). Kugelrohr distillation as above gave 5-oxa-
1-azabicyclo[4.3.0]nonane (20) as a clear oil (0.15 g, 45%). The residue
was predominantly N-(3-hydroxypropyl)pyrrolidin-2-one (21) (0.13 g,
35%). ꢀmax (neat) 3382s(br), 2948s, 2873s, 1667s, 1497m, 1466s,
1438s, 1292m, 1065s, 753s, 725s cm–1. 1H n.m.r. ꢁ (400 MHz)
1.68–1.74, m, 2H, H4; 2.05, p, 2H, J 7.7 Hz, H 2´; 2.42, t, 2H, J 8.0 Hz,
H3; 3.41, t, 4H, J 7.0 Hz, H 5, 3´; 3.54, t, 2H, J 5.8 Hz, H 1´. 13C n.m.r.
ꢁ (100 MHz) 17.72 (C 4); 29.44, 30.64 (C 2´, 3); 38.84 (C 5); 47.42
+
Mass spectrum (ESI ): m/z 258.9 (M+H)+.
A reaction of the diamine (8) (0.10 g, 0.41 mmol), BIPHEPHOS (6.4
mg, 8.13 ꢂmol) and rhodium(II) acetate dimer (0.9 mg, 2.0 ꢂmol) with
H2/CO (1 : 5) gave a yellow oil (0.10 g, 95%) whose 1H and
13C n.m.r. spectra indicated predominantly 9-benzyl-1,9-diazabicy-
clo[6.4.0]dodecane (16) with less than 10% internal derived product
(17).
+
(C 3´); 58.88 (C 1´); 175.89 (C 2). Mass spectrum (ESI ): m/z 143.9
(M+H)+. Spectroscopic data for (21) were in agreement with the litera-
ture.22
9-Oxa-1-azabicyclo[6.3.0]undecane (18)
Ring Opening Reactions
2-(Hex-5-enylamino)ethanol (6) (0.10 g, 0.70 mmol), PPh3 (3.7 mg,
14.0 ꢂmol) and rhodium(II) acetate dimer (1.5 mg, 3.5 ꢂmol) were
reacted under the standard conditions with H2/CO (1: 1). Concentration
of the solvent gave a mixture containing some 6-methyl-8-oxa-1-azabi-
cyclo[5.3.0]decane, with 13C n.m.r. ꢁ (50 MHz) 15.03 (CH3), 39.8 (C 6),
95.57 (C 7), and 9-oxa-1-azabicyclo[6.3.0]undecane (18) as a yellow
oil (0.10 g, 92%) (Found: m/z 156.1382. (C9H17NO+H)+ requires m/z
156.1388). ꢀmax (neat) 2933s, 2856s, 2808m, 1459m, 1157m, 1070m
cm–1. 1H n.m.r. ꢁ (200 MHz) 1.22–1.42, m, 6H, H 4, 5, 6; 1.43–1.75, m,
4H, H 3, 7; 2.16–2.32, m, 1H, H 2A; 2.40–2.66, m, 2H, H 2B, 11A; 3.23,
m, 1H, H11B; 3.84, dt, 2H, J 7.4, 1.8 Hz, H 10; 3.96, m, 1H, H 8. 13C
n.m.r. ꢁ (50 MHz) 25.02 (C 6); 27.42 (C 3); 29.05, 29.61 (C 4, 5); 34.03
(C 7); 52.10 (C 11); 53.23 (C 2); 64.19 (C 10); 96.63 (C 8). Mass spec-
1,5-Diazacycloheptadecane (24)
DIBAL-H (1.5 M in toluene) (0.84 mmol, 0.56 ml) was added to a
solution of 1,14-diazabicyclo[11.4.0]heptadecane (9) (0.05 mg,
0.21mmol) in toluene (5 ml) and the solution heated at reflux
overnight.13,14 NaF (0.27 g) was added at ambient temperature, fol-
lowed by water (0.1 ml) and the mixture allowed to stir for 0.5 h. The
mixture was filtered and the solids were washed with ether.
Concentration of the filtrate gave 1,5-diazacycloheptadecane (24)
which was dissolved in ether, cooled to 0°C and dry HCl(g) was
bubbled through. The ether was decanted to give the HCl salt as a white
hygroscopic solid (0.04 g, 61%) (Found: m/z 241.2639. (C15H30N2+H)+
requires m/z 241.2644). ꢀmax 3374m(br), 2922s, 2851s, 1646m, 1466s,
731m cm–1. 1H n.m.r. ꢁ (400 MHz, CD3OD) 1.32–1.57, m, 18H, H8, 9,
10, 11, 12, 13, 14, 15, 2×NH; 1.72–1.74, m, 4H, H 7, 16; 2.15, m, 2H,
H3; 3.02, m, 4H, H6, 17; 3.13, m, 4H, H 2, 4. 13C n.m.r. ꢁ (100 MHz,
CD3OD) 23.68 (C 3); 24.19, 27.26 (C 7, 16); 27.55, 30.19, 30.40, 30.45,
30.57, 30.61, 30.66 (C 8, 9, 10, 11, 12, 13, 14, 15); 45.87 (C 2, 4); C 6
+
trum (ESI ): m/z 155.8 ((M+H)+, 50%); 311.1 ((2M+H)+, 30); 333.1
((2M+Na)+, 100). Kugelrohr distillation, b.p.(oven) 100°/16 mm, gave
9-oxa-1-azabicyclo[6.3.0]undecane (18) (0.03 g, 27%). The distillation
residue was chloroform-insoluble material, the sample apparently
decomposing on heating.
+
A reaction of (6) (0.10 g, 0.70 mmol), BIPHEPHOS (21.8 mg, 28.0
ꢂmol) and rhodium(II) acetate dimer (1.5 mg, 3.5 ꢂmol) with H2/CO
(1: 1) gave 9-oxa-1-azabicyclo[6.3.0] undecane (18) (0.10 g, 92%).
and C 17 were obscured by CD3OD. Mass spectrum (ESI ): m/z 241.2
(M+H)+.
3-(Pyrrolidin-1-yl)propan-1-ol
2-(Octahydroazocin-1-yl)ethanol
Reaction of 5-oxa-1-azabicyclo[4.3.0]nonane (20) with DIBAL-H as
described above gave 3-(pyrrolidin-1-yl)propan-1-ol as an oil (0.04 g,
60%). ꢀmax (neat) 3312s(br), 2958s, 2876s, 2806s, 1460m, 1134m,
1066s, 732m cm–1. 1H n.m.r. ꢁ (400 MHz) 1.68–1.78, m, 6H, H2, 3´, 4´;
2.55–2.58, m, 4H, H 2´, 5´; 2.72, t, 2H, J 5.9 Hz, H 3; 3.79, t, 2H, J 5.4
Hz, H1. 13C n.m.r. ꢁ (100 MHz) 23.38 (C 3´, 4´); 29.58 (C 2); 54.18
A reaction of (6) (0.10 g, 0.70 mmol), BIPHEPHOS (10.9 mg, 14.0
ꢂmol) and rhodium(II) acetate dimer (1.5 mg, 3.5 ꢂmol) under the stan-
dard conditions with H2/CO (1 : 1) gave a mixture of 2-(octahydroa-
zocin-1-yl)ethanol and 2-(3-methylhexahydroazepin-1-yl)ethanol,
estimated in the ratio of 70: 30, as a yellow oil (0.08 g). Column chro-
matography (alumina: 10% EtOH/EtOAc) gave only the linear product
2-(octahydroazocin-1-yl)ethanol as a clear oil (0.04 g, 36%) (Found:
m/z 158.1541. (C9H19NO+H)+ requires m/z 158.1545). ꢀmax (neat)
3382s(br), 2929s, 2859m, 1637m, 1571s, 1490m, 1450m, 1406s,
1079m, 1050m cm–1. 1H n.m.r. ꢁ (200 MHz) 1.64–1.73, m, 10H, H3´,
4´, 5´, 6´, 7´; 2.81, t, 2H, J 5.1 Hz, 2.84, t, 2H, J 6.2 Hz, and 2.87, t, 2H,
+
(C 2´, 5´); 56.25 (C 3); 64.49 (C 1). Mass spectrum(ESI ): m/z 129.6
(M+H)+. The 1H and 13C n.m.r. spectra were in agreement with the lit-
erature.23
6-Methoxy-3,4,7,8,9,10-hexahydro-1,5-diazecine-1,5(2H,6H)-
dicarbonitrile (25)
J 5.1 Hz, H2´, 8´, 2; 3.69, t, 2H, J 5.1 Hz, H 1; 5.55, br s, 1H, OH. 13
C
Cyanogen bromide (89.5 mg, 0.85 mmol) was added to a stirred sus-
pension of 1,5-diazabicyclo[4.4.0]decane (22) (53 mg, 0.38 mmol) and
MgO (32.5 mg, 0.81 mmol) in CHCl3/MeOH (1: 1) (5 ml) under N2 fol-
lowing the procedure of Bremner.16 The reaction was kept at 40° for 14
h and then the mixture was evaporated to dryness. 2 M HCl (15 ml) was
added and the mixture extracted with CHCl3 (3×30 ml). The combined
organic extracts were dried (Na2SO4), filtered and concentrated to give
the diazecinedicarbonitrile (25) as a yellow oil (0.07 g, 82%) (Found:
m/z 245.1372. (C11H18N4O+Na)+ requires m/z 245.1378). ꢀmax (neat)
2936m, 2207s, 1451m, 1192m, 1136m, 1089m, 1040m cm–1. 1H n.m.r.
n.m.r. ꢁ (50 MHz) 25.74, 26.22, 26.39 (C 3´, 4´, 5´, 6´, 7´); 52.91 (C 2´,
+
8´); 57.92 (C 2); 59.57 (C 1). Mass spectrum (ESI ): m/z 157.9 (M+H)+.
5-Oxa-1-azabicyclo[4.3.0]nonane (20) and
N-(3-Hydroxypropyl)pyrrolidin-2-one (21)
3-(Prop-2-enylamino)propan-1-ol (19) (0.30 g, 2.61 mmol), BIPHEP-
HOS (40.8 mg, 52.2 ꢂmol) and rhodium(II) acetate dimer (5.8 mg, 13.0
mmol) were reacted with H2/CO (1: 1) under standard conditions to
give a yellow oil (0.32 g). Kugelrohr distillation, b.p.(oven) 40°/16 mm

1138
D. J. Bergmann et al.
ꢁ (400 MHz) 1.50–1.67, m, 2H, H 8A, 9A; 1.74–1.86, m, 3H, H7A, 8B,
9B; 1.93–2.00, m, 1H, H7B; 2.05–2.12, m, 2H, H 3; 3.01–3.06, m, 1H,
H2A; 3.08–3.13, m, 1H, H4A; 3.18, dt, 1H, J 6.3, 1.6 Hz, H10A;
3.26–3.34, m, 3H, H 2B, 4B, 10B; 3.45, s, 3H, OMe; 4.32, dd, 1H, J 10.1,
1.6 Hz, H6. 13C n.m.r. ꢁ (100 MHz) 22.95 (C 3); 23.19 (C 9); 24.25
(C 8); 30.68 (C 7); 40.13 (C 4); 45.33 (C 2); 54.54 (C 10); 56.02 (OMe);
Acknowledgments
We thank theAustralian Research Council for support and
provision of a postgraduate award (to D.J.B.) and Johnson
Matthey Pty Ltd for a loan of rhodium.
+
References
95.94 (C 6); 116.24 (5-CN); 117.18 (1-CN). Mass spectrum (ESI ): m/z
223.0 ((M+H)+, 30%), 245.1 ((M+Na)+, 100%).
1
Some of this work has appeared as a communication: Bergmann, D.
J., Campi, E. M., Jackson, W. R., and Patti, A. F., Chem. Commun.,
1999, 1279.
2
Verdoorn, G. H., and van Wyk, B.-E., Phytochemistry, 1992, 31,
6-Methoxy-4-oxooctahydro-1H-1,5-diazonin-1-carbonitrile (27)
1029; Meng, Q., and Hesse, M., Top. Curr. Chem., 1992, 161, 107.
3
Campi, E. M., Jackson, W. R., McCubbin, Q. J., and Trnacek, A. E.,
Cyanogen bromide (99.9 mg, 0.94 mmol) was added to a stirred
suspension of 1,5-diazabicyclo[4.4.0]decan-4-one (23) (60 mg, 0.43
mmol) and MgO (36.3 mg, 0.90 mmol) in CHCl3/MeOH (1 : 1) (5 ml)
under N2. The reaction was kept at 40° for 14 h and the product iso-
lated as above to give a yellow oil. Column chromatography (silica
gel: 20% EtOAc/light petroleum) gave the diazoninecarbonitrile (27)
as a clear oil (0.04 g, 47%) (Found: m/z 220.1051. (C9H15N3O2 + Na)+
requires m/z 220.1062.). ꢀmax (neat) 3285s, 2939s, 2208s, 1663s,
1448m, 1126m, 1085s cm–1. 1H n.m.r. ꢁ (400 MHz) 1.69, m, 2H, H 8;
1.77, m, 1H, H 7A; 2.03, m, 1H, H 7B; 2.51, dd, 1H, J 13.7, 5.9 Hz,
H 3A; 2.87, dt, 1H, J 13.6, 1.4 Hz, H 3B; 3.03, dd, 1H, J 14.9, 11.6 Hz,
H 2A; 3.30, m, 2H, H 9; 3.43, s, 3H, OMe; 3.74, ddd, 1H, J 15.1, 6.0,
1.7 Hz, H 2B; 5.05, dt, 1H, J 10.7, 3.7 Hz, H 6; 5.94, d, 1H, J 10.3 Hz,
NH. 13C n.m.r. ꢁ (100 MHz) 22.92 (C 8); 34.82 (C 7); 35.80 (C 3);
48.03 (C 2); 53.47 (C 9); 55.74 (OMe); 85.23 (C 6); 117.51 (CN);
Aust. J. Chem., 1996, 49, 219.
4
Bergmann, D. J., Campi, E. M., Jackson, W. R., Patti, A. F., and
Saylik, D., Tetrahedron Lett., 1999, 40, 5597.
5
Rische, T., Kitsos-Rzychon, B., and Eilbracht, P., Tetrahedron,
1998, 54, 2723.
6
Cuny, G. D., and Buchwald, S. L., J. Am. Chem. Soc., 1993, 115,
2066.
7
Bergmann, D. J., Campi, E. M., Jackson, W. R., McCubbin, Q. J.,
and Patti, A. F., Tetrahedron, 1997, 53, 17449.
8
Schellenberg, K. A., J. Org. Chem., 1963, 28, 3259.
9
Ojima, I., Iula, D. M., and Tzamarioudaki, M., Tetrahedron Lett.,
1998, 39, 4599; Moasser, B., Gladfelter, W. L., and Roe, D. C.,
Organometallics, 1995, 14, 3832; van Rooy, A., Kamer, P. C. J., van
Leeuwen, P. W. N. M., Goubitz, K., Fraanje, J., Veldman, N., and
Spek, A. L., Organometallics, 1996, 15, 835.
+
173.32 (C 4). Mass spectrum (ESI ): m/z 197.9 ((M+H)+, 5%); 219.9
10
Moad, G., and Benkovic, S. J., J. Am. Chem. Soc., 1978, 100, 5495,
((M+Na)+, 100%).
and references therein.
11
Illuminati, G., and Mandolini, L., Acc. Chem. Res., 1981, 14, 95;
Eliel, E. E., Wilen, S. H., and Mander, L. M., ‘Stereochemistry of
organic compounds’ pp. 675–684 (Wiley–Interscience: New York
1994).
9-Methoxy-3,4,6,7,8,9-hexahydro-1,5-oxazonine-5(2H)-carbonitrile
(28) and (4-Bromobutyl)(3؅-bromopropyl)cyanamide (29)
12
Rische, T., and Eilbracht, P., Synthesis, 1997, 1331.
Cyanogen bromide (91.8 mg, 0.87 mmol) was added to a stirred
suspension of 5-oxa-1-azabicyclo[4.3.0]nonane (20) (50 mg, 0.39
mmol) and MgO (33.3 mg, 0.83 mmol) in CHCl3/MeOH (1 : 1) (5 ml)
under N2. The reaction was kept at 40° for 14 h and the product iso-
lated as above to give a yellow oil. The 1H and 13C n.m.r. spectra indi-
cated a mixture of products including the oxazoninecarbonitrile (28) as
a significant component (13C ꢁ 54.66 (OMe), 104.05 (C 9)). Column
chromatography (silica gel: 50% EtOAc/light petroleum) gave only
(4-bromobutyl)(3´-bromopropyl)cyanamide (29) as a clear oil (0.03 g,
26%) (Found: m/z 295.9516, 297.9496, 299.9474. C8H14Br2N2
requires m/z 295.9524, 297.9504, 299.9484). ꢀmax (neat) 2938m,
2208s, 1447m, 1256m cm–1. 1H n.m.r. ꢁ (400 MHz) 1.80–1.89, m, 2H,
H 2; 1.93–2.00, m, 2H, H 3; 2.20, p, 2H, J 6.6 Hz, H 2´; 3.09, t, 2H, J
6.9 Hz, H 1; 3.20, t, 2H, J 6.7 Hz, H 1´; 3.44, t, 2H, J 6.3 Hz, H 4; 3.50,
t, 2H, J 6.2 Hz, H 3´. 13C n.m.r. ꢁ (100 MHz) 26.37 (C 2); 29.43 (C 3);
29.54 (C 3’); 30.29 (C 2´); 32.57 (C 4); 49.46 (C 1´); 51.43 (C 1);
116.81 (CN). Mass spectrum (EI): m/z 296 (C8H1479Br2N2, 1%), 298
(C8H1479Br81BrN2, 2), 300 (C8H1481Br2N2, 1), 219 (10), 217 (10), 189
(12), 175 (15), 150 (10), 137 (42), 121 (18), 111 (20), 69 (14), 55
(100).
13
Yamamoto, H., and Maruoka, K., J. Am. Chem. Soc., 1981, 103,
4186.
14
Alder, R., Heilbronner, E., Honegger, E., McEwen, A. B., Moss, R.
E., Olefirowicz, E., Petillo, P. A., Sessions, R. B., Weisman, G. R.,
White, J. M., and Yang, Z., J. Am. Chem. Soc., 1993, 115, 6580.
Hageman, H. A., Org. React., 1953, 7, 198.
15
16
Bremner, J. B., Raston, C. L, Rowbottom, G. L., White, A. H., and
Winzenberg, K. N., Aust. J. Chem., 1986, 39, 893.
Campi, E. M., Eriksson, L. K., Guy, S. T., Jackson, W. R., and
Perlmutter, P., J. Mol. Catal. A: Chem., 1999, 143, 243.
Kornblum, N., Erickson, A. E., Kelly, W. J., and Henggeler, B., J.
Org. Chem., 1982, 47, 4534.
17
18
19
20
Motorina, I. A., Darly, F., and Grierson, D. S., Synlett, 1996, 4, 389.
Castignino, E., Corsano, S., and Barton, D. H. R., Tetrahedron Lett.,
1989, 30, 2983; Mori, M., Kubo, Y., and Ban, Y., Tetrahedron, 1988,
44, 4321.
21
22
23
Leonard, N., and Musker, W. K., J. Am. Chem. Soc., 1960, 82, 5148.
Michael, J. P., and Parsons, A. S., S. Afr. J. Chem., 1993, 46, 65.
Gribble, G. W., Switzer, F. L., and Soll, R. M., J. Org. Chem., 1988,
53, 3164.