Synthesis of nitrogen heterocycles by rhodium-catalyzed hydroformylation of polymer-attached amino alkenes with syngas

Article abstract of DOI:10.1071/CH03269

Rhodium(I) phosphite catalyzed hydroaminomethylation of resin-tethered amino alkenes with H₂/CO gives moderate to good yields of five-, eight-, ten-, and thirteen-membered heterocycles. Competing hydrogenation, dimerization, or polymerization reactions were not observed using this methodology.

Full text of DOI:10.1071/CH03269

Full Paper
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2004, 57, 531–536
Synthesis of Nitrogen Heterocycles by Rhodium-Catalyzed
Hydroformylation of Polymer-Attached Amino Alkenes with Syngas
Jayamini Illesinghe,A Eva M. Campi,A W. Roy Jackson,A–C and Andrea J. RobinsonA
A School of Chemistry, Box 23, Monash University, Melbourne VIC 3800, Australia.
B Centre for Green Chemistry, Box 23, Monash University, Melbourne VIC 3800, Australia.
C Author to whom correspondence should be addressed (e-mail: W.R.Jackson@sci.monash.edu.au).
Rhodium(i) phosphite catalyzed hydroaminomethylation of resin-tethered amino alkenes with H2/CO gives
moderate to good yields of five-, eight-, ten-, and thirteen-membered heterocycles. Competing hydrogenation,
dimerization, or polymerization reactions were not observed using this methodology.
Manuscript received: 13 October 2003.
Final version: 14 January 2004.
Introduction
alkenes with in situ amines have afforded saturated amines in
good to excellent yields.[6] One intramolecular hydroamino-
methylation has also been reported. The rhodium-catalyzed
reaction of an unsaturated amine tethered by a Wang linker
to a PS-DVB (polystyrene divinylbenzene) resin with H2/CO
gave a thirteen-membered cyclic amine in excellent yield. It
should be noted that high yields were only obtained when
the reactions were stirred, and this necessitated the use of
a specially modified glass vial to prevent destruction of the
polymer beads.
We wish to report the preparation of additional nitrogen
heterocycles with ring sizes that range from small to large by
a similar intramolecular hydroaminomethylation sequence.
The use of a Wang 4-(hydroxymethyl)phenoxymethyl poly-
styrene resin has allowed us to carry out the reaction sequence
without the need for stirring. Good to excellent yields of the
resultant cyclic amines were obtained.
Tandem reaction sequences are becoming increasingly more
important in organic synthesis and are readily achieved
through the use of metal-catalyzed reactions of difunc-
tional molecules. We recently reported a highly enantio-
selective route to five- and six-membered cyclic α-amino
acids by a one-pot, single-catalyst, tandem hydrogenation–
hydroformylation cyclization sequence.[1] However, the
formation of larger sized heterocycles by this approach can
be more challenging because of competing dimerization/
polymerization processes. Recently, Doyle and coworkers
employed rhodium–carbenoid cyclization to obtain high
yields of medium and large rings, in addition to five-
and six-membered ring compounds.[2] We have previously
reported the synthesis of medium and large cyclic amines by
rhodium-catalyzed hydroformylation–reductive amination of
amino alkenes.[3] In this tandem reaction sequence, the ini-
tially formed aldehyde reacts with the tethered amine to
form an intermediate imine; this is then hydrogenated in
the presence of the rhodium catalyst to give a saturated
amine. This process, termed hydroaminomethylation,
has recently been extensively reviewed.[4] Excellent yields
of thirteen-membered ring compounds were obtained
by rhodium(i)-BIPHEPHOS catalyzed reactions of N-
benzylundec-10-enamine. Conversely, hydroaminomethyl-
ation of other amino alkenes of varying chain length gave
only modest yields of cyclized product because of compet-
ing reactions such as polymerization, dimerization, and initial
hydrogenation rather than hydroformylation of the alkene.[3]
To overcome the formation of dimers and polymers, we
re-investigated the domino reaction sequence using resin-
supported amino alkenes. Solid-phase hydroformylation of
a tethered alkene was first reported by Takahashi et al. in
the partial synthesis of muscone.[5] More recently, inter-
molecularhydroaminomethylationreactionsofresin-tethered
Results and Discussion
Hydroxymethyl Wang resin 1 was reacted with p-
carboxybenzaldehyde 2 to give the aldehyde-functionalized
resin 3 (Scheme 1). The resin was reacted with unsaturated
amines 4a–4d and the resultant imines were subsequently
reduced with sodium cyanoborohydride to give the solid-
phase amino alkenes 5. Rhodium(i)-BIPHEPHOS[7] cata-
lyzed hydroformylation of these alkenes with H2/CO gave
the polymer-attached heterocycles 6. The heterocycles were
cleaved from the resin by treatment with 95%TFA (trifluoro-
acetic acid), and isolated as their methyl ester derivatives 7
by reaction with diazomethane.
The yields of cyclic amines 7a–7d are given in Table 1.
Modest yields of amines 7b–7d, and an excellent yield of
7a were obtained. Products as a result of branch-chain alde-
hydes were not detected. The high regioselectivity observed
is in keeping with the catalyst’s preference for terminal
© CSIRO 2004
10.1071/CH03269
0004-9425/04/060531

532
J. Illesinghe et al.
P
P
O
O
O
CHO
HO2C
OH
O
1
2
3
4a H2N
4b H2N
4c H2N
4d H2N
CHO
TMOF 4a–d
NaBH3CN
O
9
P
P
O
O
O
O
O
O
Rh(I)-phosphite
CO/H2
N
NH
6
5
a–d
a–d
TFA
CH2N2
O
O
MeO
MeO
O
O
Rh(I)-phosphite
CO/H2
P
P
O
O
O
O
NH
BIPHEPHOS
N
a–d
a–d
7
8
a ꢀ CH2
b ꢀ (CH2)4
OMe
OMe
c ꢀ (CH2)3O(CH2)2
d ꢀ (CH2)9
Scheme 1.
Table 1. Yields of cyclic aminesA
For the purpose of comparing solid- and solution-phase
intramolecular hydroaminomethylation reactions, amines 4
were also converted into their N-(4-methoxycarbonyl)benzyl
derivatives 8. These amino alkenes were then subjected to
the same reaction conditions used in the resin-supported
examples. In every case more complex product mixtures
were isolated, while in the three reactions that involved
8a, 8c, and 8d, polymeric material was isolated. Surprisingly,
hydroaminomethylation of the 4-methoxycarbonyl deriva-
tive of N-benzylundecenylamine gave only a low yield of
cyclic product (14%), even though in previous solution-
phase hydroaminomethylation investigations the related
N-benzylundecenylamine afforded thirteen-membered N-
benzylazacyclotridecane in excellent yield (85%).[3]
Amine no.
Ring size
Isolated yields [%]
Resin-attached 5
Solution of 8
7a
7b
7c
7d
5
8
10
13
91
56
61
50
25B
44
49B
14B
A Hydroaminomethylation reactions on resin-attached amines 5 and free
amines 8 were performed at 80◦C for18 h with aninitial gaspressure (H2
and CO, 1 : 1) of 2.76 MPa (400 psi) in the presence of [Rh(OAc)2]2 and
BIPHEPHOS. Molar ratio of substrate to [Rh(OAc)2]2 to BIPHEPHOS
was 100 : 1 : 2 for reactions that employed amines 7a, 7b, and 7d. A
molar ratio of 50 : 1 : 2 was used in the reaction with amine 7c.
B Polymer was also obtained.
hydroformylation in the presence of the bulky phosphite
ligand.[7]
Conclusion
Products as a result of competing hydrogenation rather
than hydroformylation of the C C double bond were not
isolated, except for the reaction in which resin-tethered 5c
was involved in a 100 : 1 : 2 ratio of alkene/rhodium(i)/ligand.
A higher catalyst loading was found to completely eliminate
this side reaction. In all other cases only a single product
was obtained; this suggests that the modest yields may arise
because of insufficient cleavage from the resin or incomplete
product isolation.
Cyclic amines of varying ring size can be prepared
in moderate to excellent yields by rhodium-catalyzed
hydroaminomethylation of unsaturated amines tethered to
a Wang resin. Analogous reactions of untethered amines in
solution gave more complex product mixtures, and in three
cases polymers were formed. It is proposed that the modest
isolatedyieldsobtainedfromreactionsperformedonthesolid
phase may be due to difficulties experienced during cleavage
from the resin and/or product isolation.

Rhodium-Catalyzed Hydroformylation of Polymer-Attached Amino Alkenes with Syngas
533
Experimental
δC (100 MHz) 174.1 (C1), 139.3 (C10), 114.5 (C11), 47.3 (C2), 33.9
(C9), 29.4, 29.2, 29.1, 28.6, and 25.3 (C3, C4, C5, C6, C7, and C8). m/z
(ESI, MeOH) 183.9 ([M + H]+). Spectroscopic data were consistent
with the literature.[11]
Syntheses
Melting points are uncorrected. Infrared spectra were recorded on a
Perkin–Elmer 1600 FT-IR spectrophotometer. 1H and 13C NMR spectra
were recorded using Bruker AM-300 and DRX-400 spectrometers for
solutions in CDCl3 unless otherwise stated. Mass spectra (ESI+) were
measured on a Bruker BioApex 47 e− FTMS (Fourier-transform mass
spectrometer) with a 4.7 Tesla magnet and an Analytica electrospray
source. Mass spectra (EI) were recorded on a VG TRIO-1 Quadrupole
Mass Spectrometer at 70 eV with a source temperature of 200◦C. Micro-
analyses were performed by Chemical and Microanalytical Services Pty
Ltd, Melbourne. Merck Silica Gel 60 (230–400 mesh, no. 9385) was
used for flash chromatography. Wang resin was used as supplied by
Nova Biochem.
Undec-10-enamide (5.50 g, 30.1 mmol) was reduced with LiAlH4
(2.31 g, 72.1 mmol) according to literature procedure[11] to give undec-
10-enamine 4d as a clear oil (3.00 g, 58%). vmax (neat)/cm−1 3334s(br),
2924s, 2853s, 1641w, 1571s, 1487s, 1466s, 1319m, 992w, 910m. δH
(300 MHz) 5.81 (1H, ddt, J 16.9, 10.1, 6.6, H10), 5.04–4.89 (2H, m,
H11), 2.67 (2H, t, J 6.8, H1), 2.08–1.98 (2H, m, H9), 1.46–1.24 (16H,
m, H2, H3, H4, H5, H6, H7, H8, and 2 × NH). δC (100 MHz) 139.0
(C10), 114.0 (C11), 42.2 (C1), 33.7 and 33.8 (C2 and C9), 29.5, 29.4,
29.3, 29.0, 28.8, and 26.8 (C3, C4, C5, C6, C7, and C8). m/z (ESI,
MeOH) 170.1 ([M + H]+). Spectroscopic data were consistent with the
literature.[11]
Synthesis of Hex-5-enamine 4b
Synthesis of Methyl 4-[(Allylamino)methyl]benzoate 8a
A solution of hexen-5-ol (3.60 mL, 30.0 mmol) and diisopropyl azodi-
carboxylate (5.90 mL, 30.0 mmol) in distilled THF (20 mL) was added
in a dropwise fashion to a stirred and cooled (0◦C) suspension of phthal-
imide (4.41 g, 30.0 mmol) and triphenylphosphine (7.85 g, 30.0 mmol)
in freshly distilled THF (40 mL) under an inert atmosphere. The resul-
tant yellow solution was stirred at ambient temperature for 18 h and the
solvent was then removed under reduced pressure to give a yellow oil.
The oil was redissolved in methanol (50 mL) before hydrazine hydrate
(1.50 mL, 35.9 mmol) was added. The mixture was heated at reflux for
a further 8 h and allowed to stand overnight. Concentrated HCl (5 mL)
was then added and the reaction mixture was refluxed for a further 2 h.
After the mixture was cooled, the methanol was removed under reduced
pressure. The resultant semi-solid was dissolved in water and extracted
with dichloromethane (3 × 100 mL). The aqueous layer was concen-
trated to afford a white solid (3.90 g). 1H NMR spectroscopy of this
solid showed that it was the required hex-5-enamine hydrochloride salt.
The white solid was then dissolved in the minimum amount of water,
and NaOH pellets were added. The desired product 4b was removed by
pipette as a clear oil (2.75 g, 93%). vmax (neat)/cm−1 3377s(br), 2922s,
2856s, 1655s, 1033s, 1572m, 1501m, 1500w, 1461s, 1439s, 905s. δH
(300 MHz) 5.91–5.78 (1H, m, H5), 4.99–4.91 (2H, m, H6), 2.69 (2H, t,
J 6.6, H1), 2.07 (2H, q, J 7.0, H4), 1.48–1.41 (6H, m, H2, H3, 2 × NH).
δC (100 MHz) 139.0 (H5), 114.7 (H6), 42.3 (H1), 33.8 and 33.4 (H2 and
H4), 26.4 (H3). m/z (ESI, MeOH) 99.8 ([M + H]+). Spectroscopic data
were consistent with the literature.[8]
Prop-2-enamine (0.24 mL, 3.33 mmol) was added to a stirred solution
of p-carboxybenzaldehyde (500 mg, 3.33 mmol) in ethanol (20 mL).
The mixture was refluxed for 2 h before sodium cyanoborohydride
(NaCNBH3) (251 mg, 4.00 mmol) was added. The mixture was then
heated at reflux for a further 1 h. The mixture was concentrated under
reduced pressure to afford a white solid. Concentrated H2SO4 (5 mL)
followed by methanol (20 mL) were added to the white solid, and the
resultantmixturewasstirredfor18 hatroomtemperature. Uponremoval
of methanol under reduced pressure, the reaction mixture was basified
with NaOH (4 M) and then extracted with dichloromethane (3 × 50 mL).
The combined organic layers were dried with MgSO4, filtered, and evap-
orated to afford a yellow oil. The crude product was purified by column
chromatography (SiO2; ethyl acetate/hexane, 1 : 1) to afford the desired
product 8a (283 mg, 42%) as a yellow oil (Found: [M + H]+ 206.1178.
C12H15NO2 requires 206.1181). vmax (neat)/cm−1 3450s(br), 3077m,
3000m, 2944m, 2811m, 1717s, 1611s, 1433s, 1377m, 1278s, 1183m,
1111s, 1016m, 922m, 856w, 756s. δH (300 MHz) 8.00 (2H, d, J 8.4, H2
and H6), 7.41 (2H, d, J 8.1, H3 and H5), 5.93 (1H, ddt, J 17.2, 10.3, 6.0,
H2ꢀ), 5.25–5.10 (2H, m, H3ꢀ), 3.91 (3H, s, OCH3), 3.85 (2H, s, CH2Ph),
3.28 (2H, dt, J 6.0, 1.6, H1ꢀ). δC (100 MHz) 167.1 (CO), 144.6 (C2ꢀ),
135.7 (C4), 130.0 (C2 and C6), 129.3 (C1), 128.5 (C3 and C5), 117.4
(C3ꢀ), 52.5 (CH2Ph), 52.3 (OCH3), 51.5 (C1). m/z (ESI, MeOH) 206.1
([M + H]+).
Synthesis of Methyl 4-[(Undec-10-enylamino)methyl]benzoate 8d
The reaction was performed as described for the synthesis of methyl
4-[(allylamino)methyl]benzoate 8a, but undec-10-enamine 4d (563 mg,
3.33 mmol) was used as the starting material. After workup of the
reaction mixture, a yellow oil was isolated and purified by column
chromatography (SiO2; ethyl acetate/hexane, 1 : 1) to afford the desired
product 8d (390 mg, 33%) as a yellow oil. (Found: [M + H]+ 318.2433.
C20H31NO2 requires 318.2433). vmax (neat)/cm−1 3450s(br), 3078s,
2922s, 2856s, 1717s, 1638s, 1611s, 1572m, 1455s, 1433s, 1411s, 1278s,
1178s, 1107s, 1010s, 905s, 856s, 755s. δH (300 MHz) 7.99 (2H, d, J 8.4,
H2 and H6), 7.39 (2H, d, J 8.4, H3 and H5), 5.80 (1H, ddt, J 17.0, 10.3,
6.7, H10ꢀ), 5.04–4.89 (2H, m, H11ꢀ), 3.90 (3H, s, OCH3), 3.84 (2H, s,
CH2Ph), 2.61 (2H, t, J 7.2, H1ꢀ), 2.03 (2H, q, J 6.7, H9ꢀ), 1.55–1.21
(14H, m, H2ꢀ, H3ꢀ, H4ꢀ, H5ꢀ, H6ꢀ, H7ꢀ, and H8ꢀ). δC (100 MHz) 167.2
(CO), 146.2 (C4), 139.4 (C10ꢀ), 129.9 (C2 and C6), 128.9 (C1), 128.1
(C3 and C5), 114.3 (C11ꢀ), 53.9 (CH2Ph), 52.2 (OCH3), 49.7 (C1ꢀ),
34.0 (C9ꢀ), 30.3, 29.7, 29.6, 29.3, 29.1, and 27.5 (C2ꢀ, C3ꢀ, C4ꢀ, C5ꢀ,
C6ꢀ, C7ꢀ, and C8ꢀ). m/z (ESI, MeOH) 318.3 ([M + H]+).
Synthesis of 3-(But-3-en-1-yloxy)propan-1-amine 4c
3-(But-3-en-1-yloxy)propane nitrile was synthesized by treating buten-
3-ol (6.00 mL, 69.3 mmol) in acrylonitrile (5.50 mL, 83.16 mmol) with
Triton B (40% in MeOH, 1.2 mL) according to literature procedure.[9]
The 3-(but-3-en-1-yloxy)propane nitrile was isolated as a clear oil
(4.85 g, 56%), bp 110◦C/18 mmHg (lit.[9] 105–107◦C/18 mmHg). The
propane nitrile was then reduced with LiAlH4 to give 3-(but-3-en-1-
yloxy)propan-1-amine 4c as a clear oil (4.85 g, 97%). vmax (neat)/cm−1
3365s, 3297s, 3077s, 2864s, 1641m, 1600m, 1467w, 1432s, 1368m,
1227w, 1112s, 995m, 913s. δH (300 MHz) 5.81 (1H, ddt, J 17.0, 10.2,
6.7, H3ꢀ), 5.13–4.98 (2H, m, H4ꢀ), 3.50 (2H, t, J 6.2, H3), 3.46 (2H, t,
J 6.7, H1ꢀ), 2.78 (2H, t, J 6.7, H1), 2.32 (2H, qt, J 6.6, 1.3, H2ꢀ), 1.95
(2H, br s, 2 × NH), 1.70 (2H, quintet, J 6.3, H2). δC (100 Hz) 134.7
(C3ꢀ), 115.6 (C4ꢀ), 69.6 (C1ꢀ), 68.4 (C3), 39.1 (C1), 33.6 (C2ꢀ), 32.8
(C2). m/z (ESI, MeOH) 129.7 ([M + H]+). Spectroscopic data were
consistent with the literature.[10]
Synthesis of Undec-10-enamine 4d
Synthesis of Methyl 4-Formylbenzoate
Undec-10-enoyl chloride was treated with gaseous ammonia accord-
ing to literature procedure[11] to give undec-10-enamide as a cream
solid (5.50 g, 98%), mp 85–86◦C (lit.[11] 88.5–89◦C). vmax (KBr)/cm−1
3358s, 3078s, 2922s, 2855s, 1800s, 1638s, 1455s, 1411s, 1338w,
1127m, 989s, 961s, 911s, 722s. δH (300 MHz) 5.88–5.72 (2H, m, H10),
5.04–4.88 (2H, m, H11), 2.88 (2H, t, J 7.3, H2), 2.03 (2H, q, J 6.3, H9),
1.78–1.62 (2H, m, H3), 1.44–1.22 (12H, m, H4, H5, H6, H7, and H8).
Methyl 4-formylbenzoate was synthesized according to literature
procedure using thionyl chloride (6 mL) and p-carboxybenzaldehyde
(5.00 g, 33.3 mmol).[12] Methyl 4-formylbenzoate was isolated as an
orange-yellow solid (4.82 g, 88%), mp 60–62◦C (lit.[12] 61–63◦C).
vmax (KBr)/cm−1 3022w, 2989m, 2977w, 1727s, 1685s, 1577s, 1503s,
1435m, 1392m, 1288s, 1204s, 1108s, 1013m, 958m, 852s, 810m, 757s,
687s. δH (300 MHz, (CD3)2SO) 10.11 (1H, s, CHO), 8.16 (2H, d, J 8.5,

534
J. Illesinghe et al.
H2 and H6), 8.05 (2H, d, J 8.4, H3 and H5), 3.90 (3H, s, OCH3). δC
(100 MHz, (CD3)2SO) 193.0 (CHO), 165.5 (COOCH3), 139.1 (C1),
134.3 (C4), 129.8 and 129.7 (C2, C3, C5, and C6), 52.6 (OCH3).
DMF (1 mL). This mixture was then added to the swollen resin, and was
shaken overnight. The resultant orange suspension was filtered and the
resin was washed with DMF (5 × 10 mL). The resin was then dried for
1.5 h before trimethyl orthoformate (TMOF; 2 mL) and prop-3-enamine
4a (0.27 mL, 3.60 mmol) were added. The mixture was then agitated for
a further 18 h. Acetic acid (0.2 mL) in methanol (0.5 mL) followed by
NaCNBH3 (680 mg)inTHF(2 mL)wereaddedtotheresinmixture.This
was left to stand for 30 min and was then manually shaken for a further
30 min. The resin mixture was subjected to the general hydroformyla-
tion conditions for 18 h using BIPHEPHOS (7.2 mg, 8.00 × 10−3 mmol)
and rhodium(ii) acetate dimer (2.0 mg, 0.45 × 10−2 mmol). The vessel
pressure was released before the resin was filtered off and washed with
benzene. After the resin was dried for 1 h, the resin-tethered amine was
cleaved with TFA (10 mL, 95%). The filtrate was evaporated (using N2)
to afford an orange oil (250 mg), which was found to be the TFA salt of
4-[(pyrrolidin-1-yl)methyl]benzoic acid (Found: [M + H]+ 206.1178.
C12H15NO2 requires 206.1181). δH (300 MHz, D2O) 8.06 (2H, d, J 8.0,
H2 and H6), 7.55 (2H, d, J 8.0, H3 and H5), 4.40 (2H, s, CH2Ph), 3.49
(2H, m, H2ꢀ or H5ꢀ), 3.15 (2H, m, H2ꢀ or H5ꢀ), 2.14 (2H, m, H3ꢀ or
H4ꢀ), 1.93 (2H, m, H3ꢀ or H4ꢀ). m/z (ESI, MeOH) 206.0 ([(M + H) –
CF3COOH]+). 1H NMR spectroscopic data for the title acid were
consistent with the literature.[13]
Excess (trimethylsilyl)diazomethane was added dropwise to a solu-
tion of the above crude acid in methanol (10 mL), and the reaction
mixture was stirred for 18 h before the methanol was evaporated. The
residue was basified with saturated aqueous NaHCO3 and was then
extracted with dichloromethane (3 × 20 mL). The combined organic
layers were dried with MgSO4, filtered, and evaporated to afford an
orange oil (112 mg). The orange oil was purified by column chromato-
graphy(SiO2;ethylacetate/hexane, 1 : 3)toaffordthedesiredproduct 7a
(90 mg, 91%) as a yellow oil (Found: [M + H]+ 220.1340. C13H17NO2
requires 220.1334). δH (300 MHz) 7.99 (2H, d, J 8.2, H2 and H6), 7.42
(2H, d, J 8.1, H3 and H5), 3.91 (3H, s, OCH3), 3.70 (2H, s, CH2Ph),
2.62–2.54 (4H, m, H2ꢀ and H5ꢀ), 1.86–1.78 (4H, m, H3ꢀ and H4ꢀ). δC
(100 MHz) 167.2 (CO), 145.6 (C4), 129.9 (C2 and C6), 129.4 (C1),
129.2 (C3 and C5), 60.3 (CH2Ph), 54.3 (C2ꢀand C5ꢀ), 52.3 (OCH3),
23.6 (C3ꢀ and C4ꢀ). m/z (ESI, MeOH) 220.3 ([M + H]+). Spectroscopic
data were consistent with the literature.[14]
Synthesis of Methyl 4-[(Hex-5-enylamino)methyl]benzoate 8b
Hex-5-enamine 4b (302 mg, 3.05 mmol) was added to a stirred solution
of methyl 4-formylbenzoate (500 mg, 3.05 mmol) in ethanol (20 mL).
The mixture was refluxed for 2 h before sodium cyanoborohydride
(NaCNBH3) (220 mg, 6.10 mmol) was added. The mixture was then
heated at reflux for a further 1 h, concentrated under reduced pres-
sure, and quenched with HCl (100 mL, 1 M). Once H2 gas evolution
had ceased, the reaction mixture was basified with NaOH (4 M) and
extracted with diethyl ether (3 × 50 mL). The combined organic layers
were dried with MgSO4 and evaporated to afford the desired prod-
uct 8b (602 mg, 80%) as an orange oil (Found: [M + H]+ 248.1642.
C15H21NO2 requires 248.1650). vmax (neat)/cm−1 3333s(br), 3066m,
2911s, 2855s, 1716s, 1638s, 1611s, 1577m, 1433s, 1416s, 1277s, 1172s,
989s, 911s, 727s. δH (300 MHz) 7.99 (2H, d, J 8.4, H2 and H6), 7.39
(2H, d, J 8.4, H3 and H5), 5.80 (1H, m, H5ꢀ), 5.04–4.90 (2H, m, H6ꢀ),
3.91 (3H, s, OCH3), 3.84 (2H, s CH2Ph), 2.62 (2H, t, J 7.1, H1ꢀ), 2.05
(2H, q, J 7.0, H4ꢀ), 1.58–1.36 (4H, m, H2ꢀ and H3ꢀ). δC (100 MHz) 167.2
(CO), 146.2 (C4), 138.9 (C5ꢀ), 128.9 (C1), 129.9 and 128.1 (C2, C3,
C5, and C6), 114.7 (C6ꢀ), 53.9 (CH2Ph), 52.2 (OCH3), 49.5 (C1ꢀ), 33.8
(C4ꢀ), 29.7 and 26.7 (C2ꢀ and C3ꢀ). m/z (ESI, MeOH) 248.0 ([M + H]+).
Synthesis of Methyl 4-{[(3-(But-3-en-1-yloxy)propyl)amino]methyl}-
benzoate 8c
This reaction was carried out as described for methyl 4-[(hex-
5-enylamino)methyl]benzoate 8b, but 3-(but-3-en-1-yloxy)propan-1-
amine 4c (390 mg, 3.05 mmol) was used as the starting material.
After workup of the reaction mixture, an orange oil (602 mg) was
isolated. Subsequent purification of the crude product by column chro-
matography afforded the •desired product 8c as an orange oil (278 mg,
•
35%). (Found: [M + H]+ 278.1751. C16H23NO3 requires [M + H]+
278.1756). vmax (neat)/cm−1 3333sb, 3077m, 2944s, 2855sm 1727s,
1716s, 1644w, 1611s, 1433s, 1278s, 1106s, 1022m, 917s. δH (300 MHz)
7.99 (2H, d, J 8.4, H2 and H6), 7.40 (2H, d, J 8.5, H3 and H5), 5.80
(1H, m, H3ꢀꢀ), 5.12–4.97 (2H, m, H4ꢀꢀ), 3.91 (3H, s, OCH3), 3.85 (2H,
s, CH2Ph), 3.51 (2H, t, J 6.8, H1ꢀꢀ or H3ꢀ), 3.46 (2H, t, J 6.8, H1ꢀꢀ or
H3ꢀ), 2.73 (2H, t, J 6.8, H1ꢀ), 2.49 (1H, s, NH), 2.31 (2H, qt, J 6.7,
1.3, H2ꢀꢀ), 1.80 (2H, quintet, J 6.4, H2ꢀ). δC (100 MHz) 167.2 (CO),
145.7 (C4), 135.4 (C3ꢀꢀ), 128.9 (C1), 129.9 and 128.1 (C2, C3, C5, and
C6), 116.6 (C4ꢀꢀ), 70.3 and 69.7 (C3ꢀ and C1ꢀꢀ), 53.7 (CH2Ph), 52.2
(OCH3), 47.2 (C1ꢀ), 34.3 and 29.9 (C2ꢀ and C2ꢀꢀ). m/z (ESI, MeOH)
278.1 ([M + H]+).
Method B
Methyl 4-[(allylamino)methyl]benzoate 8a (150 mg, 0.73 mmol) was
hydroformylated in the presence of BIPHEPHOS (3.2 mg) and rho-
dium(ii) acetate dimer (11.5 mg) according to the general conditions
outlined above.After 18 h, the vessel pressure was released to reveal that
theglasssleevewaslinedwithinsolublepolymericmaterial.Theremain-
ing solution was concentrated to afford a brown oil (70 mg). Purification
by column chromatography (SiO2; ethyl acetate/hexane, 1 : 1) afforded
the desired product 7a (40 mg, 25%) as a yellow oil. Spectroscopic data
were consistent with those described for 7a obtained by method A.
General Conditions for Reactions with H2/CO
Reactions were carried out in a 100 mL Parr autoclave with a glass
sleeve that contained a stirrer bead. The substrate (0.1–0.3 g, approxi-
mately 1 mmol), rhodium catalyst precursor ([Rh(OAc)2]2), and ligand
(BIPHEPHOS)[7] (in a ratio of 100 : 1 : 2) were placed in the autoclave
under an atmosphere of nitrogen, and deoxygenated benzene (10 mL)
was then added to the autoclave.
The vessel was flushed and evacuated three times with 200 psi
(1.38 Mpa) H2/CO (1 : 1 molar mixture), and was then pressurized to
400 psi (2.76 MPa). The reaction mixtures were kept at 80◦C for 20 h
before the autoclave was cooled, the gases released, and the contents
analyzed as reported.
Synthesis of Methyl 4-[(Azacyclooctan-1-yl)methyl]benzoate 7b
Method A
This reaction was performed in the manner described for methyl 4-
[(pyrrolidin-1-yl)methyl]benzoate 7a, but hex-5-enamine 4b (356 mg,
3.60 mmol) was used as the starting material. Subsequent TFA (6 mL,
95%) cleavage of the amine from the resin afforded [t1h5e] TFA salt
of 4-[(azacyclooctan-1-yl)methyl]benzoic acid (157 mg)
as a clear
oil (Found: [(M + H) – CF3COOH]+ 248.1648. C15H21NO2 requires
248.1650. m/z (ESI, MeOH) 248.3 ([M + H) – CF3COOH]+).
Esterification was performed in the manner described for methyl
4-[(pyrrolidin-1-yl)methyl]benzoate 7a to afford an orange oil (95 mg).
Purification of the crude product by column chromatography (SiO2;
ethyl acetate/hexane, 1 : 1) afforded the title methyl ester 7b (66 mg,
56%) as a yellow oil (Found: [M + H]+ 262.1803. C16H23NO2 requires
262.1807). vmax (neat)/cm−1 2911s, 2856s, 2789s, 1722s, 1611s,
1572m, 1433s, 1411m, 1350m, 1278s, 1105s, 1017s, 967s, 850m, 756s.
δH (300 MHz) 7.98 (2H, d, J 8.4, H2 and H6), 7.44 (2H, d, J 8.1, H3 and
H5), 3.91 (3H, s, OCH3), 3.64 (2H, s, CH2Ph), 2.54 (4H, t, J 5.8, H2ꢀ and
Synthesis of Methyl 4-[(Pyrrolidin-1-yl)methyl]benzoate 7a
Method A
Wang resin (500 mg, 0.45 mmol) was pre-swollen in DMF (3 × 10 mL),
and
a
solution of 4,4ꢀ-dimethylaminopyridine (DMAP; 27 mg,
0.23 mmol) in DMF (1 mL) was then added to the resin. In a sepa-
rate vial, p-carboxybenzaldehyde 2 (338 mg, 0.25 mmol) was dissolved
in DMF (1 mL), and was then added to a solution of DMAP (54 mg,
0.45 mmol) and 1,3-diisopropylcarbodiimide (0.35 mL, 2.25 mmol) in

Rhodium-Catalyzed Hydroformylation of Polymer-Attached Amino Alkenes with Syngas
535
H8ꢀ), 1.72–1.46 (10H, m, H3ꢀ, H4ꢀ, H5ꢀ, H6ꢀ, and H7ꢀ). δC (100 MHz)
167.4 (CO), 147.2 (C4), 129.7 (C2 and C6), 129.1 (C3 and C5), 128.9
(C1), 63.6 (CH2Ph), 54.6 (C2ꢀ and C8ꢀ), 52.2 (OCH3), 28.0 and 26.3
(C3ꢀ, C4ꢀ, C5ꢀ, C6ꢀ and C7ꢀ). m/z (ESI, MeOH) 262.4 ([M + H]+).
general conditions outlined above. After 18 h, the vessel pressure was
released and the reaction solvent was concentrated to afford a brown
oil (183 mg). The crude product was purified by column chromato-
graphy (SiO2; ethyl acetate/hexane, 1 : 5) to give the desired product
7c (100 mg, 49%) as a yellow oil. Spectroscopic data were consistent
with those described for 7c obtained by method B.
Method B
Methyl 4-[(hex-5-enylamino)methyl]benzoate 8b (176 mg, 0.71 mmol)
was hydroformylated in the presence of BIPHEPHOS (3.1 mg) and
rhodium(ii) acetate dimer (11.2 mg) according to the general condi-
tions outlined above. After 18 h, the vessel pressure was released and
the reaction solvent was concentrated to afford a brown oil (111 mg).
Purification of the crude product by column chromatography (SiO2;
ethyl acetate/hexane, 1 : 1) afforded the desired product 7b (82 mg, 44%)
as a yellow oil. Spectroscopic data were consistent with those described
for 7b obtained by method A.
Synthesis of Methyl 4-[(Azacyclotridecan-1-yl)methyl]benzoate 7d
Method A
The reaction was performed in the manner described for methyl
4-[(pyrrolidin-1-yl)methyl]benzoate 7a, but undec-10-enamine 4d
(608 mg, 3.6 mmol) was used as the starting material. Subsequent TFA
(6 mL, 95%) cleavage of the amine from the resin afforded the TFA salt
of 4-[(azacyclotridecan-1-yl)methyl]benzoic acid (247 mg) as a clear
oil (m/z 306.3 [M + H]+). Esterification was carried out in the manner
described for methyl 4-[(pyrrolidin-1-yl)methyl]benzoate 7a to afford
an orange oil (150 mg). The crude product was purified by column
chromatography (SiO2; ethyl acetate/hexane, 1 : 5) to afford the title
compound 7d (74 mg, 50%) as a yellow solid, mp 98–102◦C (Found:
[M + H]+ 332.2587. C21H33NO2 requires 332.2589). vmax (neat)/cm−1
3411s(br), 2966m, 2911s, 2844s, 2777m, 1716s, 1611m, 1561s, 1461s,
1433s, 1272s, 1100s. δH (300 MHz) 7.97 (2H, d, J 8.2, H2 and H6), 7.40
(2H, d, J 8.1, H3 and H5), 3.90 (3H, s, OCH3), 3.56 (2H, s, CH2Ph),
2.42–2.28 (4H, m, H2ꢀ and H13ꢀ), 1.50–1.18 (20H, m, H3ꢀ, H4ꢀ, H5ꢀ,
H6ꢀ, H7ꢀ, H8ꢀ, H9ꢀ, H10ꢀ, H11ꢀ, and H12ꢀ). δC (100 MHz) 167.2 (CO),
138.9 (C4), 129.4 (C2 and C6), 129.1 (C1), 128.7 (C3 and C5), 59.2
(CH2Ph), 55.8 and 53.8 (C2ꢀ and C13ꢀ), 52.7 (OCH3), 29.5, 29.3, 27.1,
and 27.0 (C3ꢀ, C4ꢀ, C5ꢀ, C6ꢀ, C7ꢀ, C8ꢀ, C9ꢀ, C10ꢀ, C11ꢀ, and C12ꢀ). m/z
(ESI, MeOH) 332.3 ([M + H]+).
Synthesis of Methyl 4-(1,5-Oxazanan-5-ylmethyl)benzoate 7c
Method A
The reaction was performed in the manner described for methyl
4-[(pyrrolidin-1-yl)methyl]benzoate 7a, but 3-(but-3-en-1-yloxy)
propan-1-amine 4c (461 mg, 3.60 mmol) was used as the starting
material. Subsequent TFA (6 mL, 95%) cleavage of the amine from
the resin afforded 4-{[(3-(butan-1-yloxy)propyl)amino]methyl}benzoic
acid (196 mg) as a clear oil and only trace amounts of the title benzoate
7c. Esterification of the crude reaction by-product was performed in
themannerdescribedformethyl4-[(pyrrolidin-1-yl)methyl]benzoate7a
to afford methyl 4-{[(3-(butan-1-yloxy)propyl)amino]methyl}benzoate
(87 mg, 70%) (Found: [M + H]+ 280.1908. C16H25NO3 requires
280.1913). vmax (neat)/cm−1 3322s(br), 2944s, 2856s, 1722s, 1611s,
1455s, 1433s, 1367m, 1277s, 1183m, 1111s, 1017s, 967m, 750s. δH
(300 MHz) 7.97 (2H, d, J 8.4, H2 and H6), 7.38 (2H, d, J 8.5, H3 and
H5), 3.90 (3H, s, OCH3), 3.83 (2H, s, CH2Ph), 3.47 (2H, t, J 6.2, H3ꢀ
or H1ꢀꢀ), 3.38 (2H, t, J 6.6, H3ꢀ or H1ꢀꢀ), 2.71 (2H, t, J 6.8, H1ꢀ), 1.77
(2H, quintet, J 6.5, H2ꢀ), 1.52 (2H, quintet, J 7.0, H2ꢀꢀ), 1.32 (2H, sex-
tet, J 7.4, H3ꢀꢀ), 0.89 (3H, t, J 7.4, H4ꢀꢀ). δC (100 MHz) 167.3 (CO),
146.2 (C4), 129.9 (C2 and C6), 128.9 (C1), 128.1 (C3 and C5), 71.0 and
69.7 (CH2Ph and C1ꢀ), 53.9 (C3ꢀ), 52.2 (OCH3), 47.3 (C1ꢀꢀ), 32.0 and
30.2 (C2ꢀ and C2ꢀꢀ), 19.6 (C3ꢀꢀ), 14.1 (C4ꢀꢀ). m/z (ESI, MeOH) 280.2
([M + H]+).
Method B
Methyl 4-[(undec-10-enylamino)methyl]benzoate 8d (341 mg,
1.07 mmol) was hydroformylated in the presence of BIPHEPHOS
(34 mg, 4.3 × 10−2 mmol) and rhodium(ii) acetate dimer (9.5 mg,
2.15 × 10−2 mmol) according to the general procedure described above.
After 18 h, the vessel pressure was released to reveal that the glass sleeve
was lined with insoluble polymeric material. The remaining solution
was concentrated to afford a brown oil (356 mg). The crude product was
purified by column chromatography (SiO2; ethyl acetate/hexane, 1 : 5)
to afford the title compound 7d (50 mg, 14%) as a yellow oil. Spectro-
scopic data were consistent with those described for 7d obtained by
method A.
Method B
The hydroformylation reaction was performed as described in method
A, but with a higher catalyst loading [BIPHEPHOS (14.4 mg,
16 × 10−3 mmol) and rhodium(ii) acetate (4.0 mg, 9.0 × 10−3 mmol)].
Subsequent TFA (6 mL, 95%) cleavage of the amine from the resin
afforded 4-(1,5-oxazanan-5-ylmethyl)benzoic acid (286 mg) as a clear
oil. Esterification was carried out in the manner described for methyl 4-
[(pyrrolidin-1-yl)methyl]benzoate 7a to afford an orange oil (110 mg).
Purification of the crude product by column chromatography (SiO2;
ethyl acetate/hexane, 1 : 1) afforded the title compound 7c (80 mg, 61%)
as a yellow oil (Found: C 70.0, H 8.7, N 4.8, [M + H]+ 292.1902.
C17H25NO3 requires C 70.0, H 8.7, N 4.8%, [M + H]+ 292.1913).
vmax (neat)/cm−1 3000s(br), 2922s, 2844s, 1722s, 1605s, 1600w, 1427s,
1272s, 1106s, 1022s, 944m, 855m, 761s. δH (300 MHz) 7.99 (2H, d,
J 8.3, H2 and H6), 7.42 (2H, d, J 8.1, H3 and H5), 3.91 (3H, s, OCH3),
3.65 (4H, t, J 5.3, H4ꢀ and H6ꢀ), 3.55 (2H, s, CH2Ph), 2.53 (2H, t, J 6.1,
H2ꢀ or H10ꢀ), 2.39 (2H, t, J 5.3, H2ꢀ or H10ꢀ), 1.74–1.45 (8H, m, H3ꢀ,
H7ꢀ, H8ꢀ, and H9ꢀ). δC (100 MHz) 167.4 (CO), 146.1 (C4), 129.7 (C2
and C6), 129.4 (C3 and C5), 128.9 (C1), 72.8 (CH2Ph), 66.6 and 61.1
(C4ꢀ and C6ꢀ), 52.2 (OCH3), 55.3 and 48.7 (C2ꢀ and C10ꢀ), 27.3 and
26.2 (H3ꢀ, H7ꢀ, H8ꢀ, and H9ꢀ). m/z (ESI, MeOH) 292.1 ([M + H]+).
Acknowledgments
We thank the Australian Research Council for the award of a
Discovery Grant and for provision of a postgraduate research
award (to J.I.), and Johnson Matthey for the loan of precious
metals.
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