Model studies for the synthesis of the antibiotic lactonamycin and the discovery of new reactions and mechanisms for the construction of substituted heterocycles

Article abstract of DOI:10.1016/j.tet.2010.05.051

A new and highly efficient route for the construction of a model for the synthesis of lactonamycin 1 is reported. The chemistry has been utilised for the synthesis of heterocyclic rings, and new reactions for the synthesis of dienes and alkynes are report

Full text of DOI:10.1016/j.tet.2010.05.051

Tetrahedron 66 (2010) 6526e6533
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Model studies for the synthesis of the antibiotic lactonamycin and the
discovery of new reactions and mechanisms for the construction
of substituted heterocycles
*
Philip J. Parsons , Jonathan Board, Davide Faggiani, Peter B. Hitchcock, Lewis Preece,
Alexander J. Waters
Division of Chemistry, School of LifeSciences, University of Sussex, Falmer, Brighton, East Sussex BN1 9QJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A new and highly efficient route for the construction of a model for the synthesis of lactonamycin 1 is
reported. The chemistry has been utilised for the synthesis of heterocyclic rings, and new reactions for
the synthesis of dienes and alkynes are reported.
Received 2 March 2010
Received in revised form 6 May 2010
Accepted 13 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Available online 20 May 2010
Keywords:
Cyclisation
Cascade
Lactonamycin
Antibiotic
New reactions
1. Introduction
Lactonamycin 1 was isolated from bacterium Streptomyces
rishiriensis and its structure was reported by Matsumoto in 1996.1
Lactonamycin was shown to possess potent antibiotic activity and
good efficacy against Gram-positive bacteria including most nota-
bly Methicillin-Resistant Staphylococcus Aureus (MRSA) and Van-
comycin-Resistant Enterococcus (VRE).1 Matsumoto and co-workers
published the structure of lactonamycin 1 in detail in 1999 together
with its biological properties and production procedures.2,3 In
2003, an analogue of lactonamycin, lactonamycin Z 2 was isolated
from pine wood samples collected from Hamsterley Forest in En-
gland.4 Although lactonamycin Z 2 showed weak Gram-positive
activity, it proved to be very active against gastric adenocarcinoma
(HMO2) (IC50, 0.19 mg mLꢀ1) in human cell lines.
The biological profile of the lactonamycins is of great interest
and because the search for new antibiotics is now of paramount
importance due to the dramatic increase in post operative hospital
infections5 great interest has been shown from the chemical
community in the synthesis of the lactonamycins.
In 2002, Behar and Deville published a synthesis of the ABCD ring
system precursor of lactonamycin 1.6 A different approach was
published by Kelly and co-workers,7 which involved a DielseAlder
reaction as the key step for the formation of the ABCD ring. Kelly and
his co-workers subsequently published a route to the EF ring system
of lactonamycin 18 but they have hitherto not reported a total
synthesis of lactonamycin 1. Notable contributions to the synthesis
of lactonamycin 1 have also been made by Barrett and Danishefsky.
* Corresponding author. E-mail address: P.J.Parsons@sussex.ac.uk (P.J. Parsons).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.05.051

P.J. Parsons et al. / Tetrahedron 66 (2010) 6526e6533
6527
1.1. Cyclisation studies and the new synthetic approach
Br
R
We devised a novel approach to the core of lactonamycin 1 to-
gether with an approach to the total synthesis of this important
natural substance9 (Scheme 1).
R = Br,
Boc
N
O
R
Me
Boc
Me
N
O
Me
11
Me
N
O
OH
N
O
MeO
OH
O
MeO
O
O
O
O
OH
OH
HO
With the cyclisation precursor 10 in hand, we investigated a radical
cascade sequence mediated with tri-n-butyltin hydride (Scheme 3).
O
MeO
3
4
O
MeO
OH
OH
O
O
O
Me
N
O
H
OH
O
Me
N
Me
N
SiMe3
OH
MeO
O
i
Br
OH
Br
O
5
SiMe3
6
SiMe3
Br
10
12
Scheme 1.
Scheme 3. Reagents and conditions: (i) Bu3SnH, AIBN, benzene (14%).
Retrosynthetic analysis of lactonamycin 3 led to the idea that
a palladium10 or tin11 mediated cyclisation of the ene diyne 5 would
after suitable chemical transformations give the tetracycle 4. We
envisaged that the ene diyne 5 could easily be prepared from the
aldehyde 6. In order to test this hypothesis the chemistry outlined
in Scheme 2 was carried out.
The reaction between tri-n-butyltin hydride and the alcohol 10 in
boiling benzene gave the tetracyclic amide 12 in 14% isolated yield.
This result was surprising because the lactam 12 was not
the expected product 15 of the radical cyclisation depicted in
Scheme 4.
O
Me
N
OH
OH
H
Me
N
Me
N
N
i, ii, iii
iv
O
O
Me
Br
Br
7
8
Br
SiMe3
SiMe3
OH
OH
13
10
Me
NHHCl
Me
N
v
Me
N
Me
Boc
N
OH
OH
H
O
O
Br
Br
9a
9
OH
SiMe3
SiMe3
Me
15
14
vi
N
O
Scheme 4.
Br
10
SiMe3
When the alcohol 10 was heated in toluene solution in the absence
of tri-n-butyltin hydride, the tetracyclic lactam 12 was formed
in 41% isolated yield. In order to prevent the acid catalysed
decomposition of intermediates or the starting material with
liberated hydrogen bromide, we elected to carry out the reaction in
the presence of the high boiling epoxide epoxyhexene. In the
presence of epoxyhexene in hot toluene the alcohol 10 underwent
cyclisation to give the amide 12 in 76% yield. By analogy, epoxy-
propene served as an efficient acid trap in Corey’s synthesis of
gibberellic acid.14
Scheme 2. Reagents and conditions: (i) n-BuLi, (1.05 equiv), THF, ꢀ78 ꢁC; (ii) CuCN,
(1.05 equiv), ꢀ78 ꢁC to ꢀ40 ꢁC; (iii) 2,3-di bromopropene, (1.2 equiv), ꢀ78 ꢁC to room
temperature, HCl/H2O quench then 2 M HC1 (73%); (iv) LiC^CeCH2NMe(Boc), then
tBuBr (80%); (v) 4 M HCl dioxane (2 equiv), 2 h (69%); (vi) TMSeC^CeCO2H, oxalyl
chloride/DMF/Et3N (86%).
Treatment of the aminal 7 with n-butyllithium in tetrahy-
drofuran at ꢀ78 ꢁC, followed by transmetallation with cuprous
cyanide12 gave an intermediate cuprate, which upon reaction
with 2,3-dibromopropene, gave the aldehyde 8 after acidic
workup. Addition of the lithium salt of N-Boc-methylpropargyl-
amine13 to the aldehyde 8 followed by workup with tert-butyl
bromide gave the alcohol 9 in high yield. tert-Butyl bromide acts
as a bulky proton source and is entirely neutral as a quenching
agent.9 Other methods that were used to quench this reaction
gave lower yields of the desired alcohol 9 and when ammonium
chloride in water was used to work up the reaction mixture the
ether 11 was isolated.
In order to rule out the possibility of an acid catalysed cyclisa-
tion the alcohol 18 was prepared according to Scheme 5.
The alkyne 18 was heated in boiling toluene for four hours to
give two products 12 and 19.
Me
N
Me
N
OH
O
O
O
The alcohol 9 was treated with hydrogen chloride in dioxane to
afford the amine hydrochloride salt 9a. Treatment of the alcohol 9a
with trimethylsilylpropynoyl chloride generated from the parent acid
and oxalyl chloride in dimethylformamide gave the desired alchol 10.
SiMe3
SiMe3
19
12

6528
P.J. Parsons et al. / Tetrahedron 66 (2010) 6526e6533
Me
N
removing the benzylic hydrogen in 10 by benzylic oxidation to
afford the ketone 24 (Scheme 7).
O
i, ii
iii
N
SiMe3
Me
O
OH
Me
Br
7
Me
N
16
O
N
O
i
OH
OH
Me
Me
NBoc
Br
Br
iv
N
24
10
Boc
SiMe3
SiMe3
Scheme 7. Reagents and conditions: (i) MnO2 (21 equiv), DCM (97%).
17a
17
SiMe3
OH
OH
When the ketone 24 was heated in toluene solution for 6 h under
reflux a remarkable transformation was observed; the alkyne 25
was isolated in 30% isolated yield (Scheme 8).
Me
NH.HCl
v
Me
17b
N
O
Me
N
O
O
Me
N
i
vi
O
Br
SiMe3
24
Br
25
18
SiMe3
Scheme 8. Reagents and conditions: (i) Toluene, reflux, 6 h (30%).
Scheme 5. Reagents and conditions: (i) n-BuLi (1.05 equiv), CuCN (1.05 equiv); Me3
-
SiC^CeCH2Br (1.1 equiv), THF ꢀ60 ꢁ
C (69%); (ii) H2O; (iii) LiC^CeCH2NMe(Boc),
The formation of the alkyne 25 was totally unexpected and the
mechanism outlined in Scheme 9 was proposed to account for this
unprecedented transformation.
tBuBr, ꢀ95 ꢁC (90%); (iv) MeONa (0.3 equiv), MeOH, DCM 1:1 (97%); (v) HCl, Et2O
(60%); (vi) oxalyl chloride (1.1 equiv), DMF, TMSC^CeCO2H (28%).
Me
1.2. A mechanistic discussion and the discovery of new
reactions
N
O
O
Me
N
O
SiMe3
O
The isolation of the ketone 19 was very interesting because this
indicated that a radical mechanism could be in operation. The
isolation of 12 in low yield in the presence of tri-n-butyltin hydride
also points towards a radical cyclisation (Scheme 6).
Br
SiMe3
Br
24
26
Me
N
Me
N
O
Me
N
O
OH
O
SiMe3
SiMe3
O
Me
N
O
O
H
HO
SiMe
Br
27
28
Br
20
Me
N
18
SiMe
O
Me
N
Me
N
Me
N
OH
OH
OH
+
CO + BnSiMe3
O
O
O
SiMe
SiMe
SiMe
Br
25
Scheme 9.
23
21
22
Me
N
Me
O
O
N
OH
O
The biradical 26 could be formed as described in Scheme 6; instead
of hydrogen atom abstraction the alkenyl radical could add to the
carbonyl group as shown in structure 26 to form the new biradical
27. Fragmentation of 27 would give the acyl silane 28, which on loss
of carbon monoxide and benzylsilane (from benzyl radical addition
to silicon) would give the observed product 25.
SiMe
SiMe
19
12
Scheme 6.
In order to further investigate the cyclisation the deuterated
The alkyne 18 could cyclise to give a concentration of the bir-
adical 20, which in turn could give the biradical 21 by hydrogen
atom abstraction. The biradical 21 could then cyclise to give the
intermediate 23 and hence isomerise to the phenol 12 or by hy-
drogen atom abstraction from the solvent (toluene) from the enol
22, which would form the ketone 19 by tautomerism. We decided
to test the mechanism of this intriguing reaction further by
amide 32 was prepared according to Scheme 10.15
When the amide 32 was heated in hot toluene, cyclisation oc-
curred to give the dihydrofuran 33 in 94% isolated yield (Scheme 11).
The deuterium transfer observed in lactam 33 coupled with
a slower rate of reaction compared with its hydrogen analogue adds
support to a concerted mechanism, which could operate in the ab-
sence of a radical stabilizing aromatic ring (Scheme 12).

P.J. Parsons et al. / Tetrahedron 66 (2010) 6526e6533
6529
Me
monitored using analytical thin layer chromatography with vis-
ualisation by UV light and either alkaline potassium permanga-
nate (KMnO4), vanillin or phosphomolybdic acid (PMA) dips.
Reaction solvents were purified and dried according to literature
methods. Tetrahydrofuran and diethyl ether were distilled from
sodium with benzophenone as indicator; dichloromethane and
acetonitrile were distilled from calcium hydride. Petrol refers to
distilled petroleum 40e60 ꢁC. All other solvents and reagents
were used as supplied. Flash chromatography was performed
using silica gel 60, 230e400 mesh. 1H NMR spectra were recor-
ded on a Bruker 300 MHz machine operating at ambient probe
temperature using an internal deuterium lock. Chemical shifts
were reported in parts per million (ppm) using residual solvent
as an internal standard. Standard abbreviations were used
throughout (s singlet; br d broad doublet, br s broad singlet;
d doublet; dd doublet of doublets; dt doublet of triplets; dq
doublet of quartets; t triplet; q quartet; m multiplet). Coupling
constants were measured in hertz (Hz). 13C NMR spectra were
recorded at 75 MHz. Chemical shifts were reported in parts per
million (ppm). Dept and correlation experiments were used for
assignment of spectra. In some cases amide splitting caused
doubling of peaks. Suppression of this was not possible using
conventional variable temperature experiments and as such the
relevant peaks have been assigned together. ESI mass spectra
were recorded on a Bruker Daltonics Apex III spectrometer with
methanol as solvent. EI mass spectra were recorded on a Fisons
VG Autospec spectrometer. Infra red spectra were recorded on
Me
N
N
D
i
Boc
Boc
D
D
OH
29
30
D
D
O
D
O
Me
N
SiMe3
Me
N
iii, iv
ii
Boc
O
31
32
Scheme 10. Reagents and conditions: (i) n-BuLi, THF, ꢀ78 ꢁC, paraformaldehyde D2
(94%); (ii) NaH, allyl bromide (quant); (iii) TFA, CH2Cl2; (iv) Et3N, TMSC^CCOCl (68%).
Me
D
D
O
N
D
Me
N
SiMe3
i
O
O
O
SiMe3
D
32
33
Scheme 11. Reagents and conditions: (i) Toluene, 110 ꢁC, 3.5 h, (94%).
Me
N
Me
N
O
O
Me
N
D
O
D
D
SiMe3
SiMe3
O
D
D
D
O
O
SiMe3
a
Perkin ELMER Spectrum One FT-IR spectrometer. Crystal
35
36
34
structures were obtained from a Bruker/Enraf Nonius FR590
KappaCCD. Structures were named using the ACD labs ‘ACD/
IUPAC Name v8.05’. The result of ACD/IUPAC Name v8.05 was
obtained using the ACD/I-Lab service.
stepwise
path b
path c
Me
N
O
Me
N
3.1.1. 2-(2-Bromophenyl)-1,3-dimethylimidazolidine (7). A solution
of 2-bromobenzaldehyde (10.1 g, 55 mmol) and N,N0-dimethyl-
ethylenediamine (7.0 ml. 66 mmol) in ethanol (100 ml) was stirred
at room temperature for 18 h. The reaction mixture was dried over
MgSO4 and the solvent was removed under reduced pressure to
O
SiMe3
Me
N
concerted
path a
D
D
D
SiMe3
O
O
O
D
SiMe3
O
D
D
D
33
32
37
€
give a yellow oil. This was purified using Kugelrohr distillation
(0.2 mbar, 110 ꢁC) to yield 7 (12.9 g, 92%) as a transparent colourless
oil. Spectra were consistent with those previously reported. IR
(neat) v (cmꢀ1): 3396, 3134, 3064, 2970, 2942, 2840, 2778, 2695,
2671, 2627, 2566, 2473, 1670, 1589, 1568; dH (300 MHz, CDC13):
7.72e7.15 (dd, 1H, J1¼7.8 Hz, J2¼1.7 Hz, Ar), 7.51e7.48 (dd, 1H,
J1¼8.0 Hz, J2¼0.9 Hz, Ar), 7.35e7.30 (m, 1H, Ar), 7.16e7.11 (m, 1H,
Ar), 4.05 (s, 1H, 7-CH), 3.40e3.34 (m, 2H, 8-CH2), 2.65e2.60 (m, 2H,
9-CH2), 2.21 (s, 6H, 10-CH3-11-CH3). dC (75 MHz, CDC13): 138.6 (q,
Ar), 132.1 (CH, Ar), 129.6 (CH, Ar), 127.8 (CH, Ar), 125.4 (q, Ar), 88.3
(CH, 7-C), 53.4 (CH3, 8-C-9-C), 39.4 (10-C-11-C). MS (EI) m/z (rel
int.): 255 (M), 210, 132, 88, 42. HRMS (ESIþ): calcd for C11H15N2Br,
m/z 255.0491, found 255.0499.
Scheme 12.
In Scheme 12 concerted path a would proceed by an intra-
molecular ene reaction to give the allene intermediate 37, which
could also result from the radical pathway b. Either a DielseAlder
reaction from allene 37 to lactam 33 could occur, or the cycload-
dition pathway from the biradical 36 would also result in the for-
mation of the lactam 33.16e20
2. Conclusion
We have discovered a new cyclisation reaction together with
a novel route to substituted alkynes. The mechanism of the cyc-
lisation of the aryl substituted diynes appear to follow a radical
pathway, which is also postulated for the formation of the alkyne
25. The facile formation of the lactam 33 occurs with deuterium
transfer and the cyclisation requires a longer reaction time (3.5 h)
compared to less than one hour for its hydrogen analogue. The
formation of 33 is consistent with a radical or a concerted
pathway.
3.1.2. 2-(2-Bromoprop-2-en-1-yl)benzaldehyde (8). n-Butyllithium
(2.5 M in hexanes, 16.5 ml, 41.2 mmol) was added to a cooled
(ꢀ78 ꢁC) solution of 2-(2-bromophenyl)-1,3-dimethylimidazolidine
(7) (10.0 g, 39.2 mmol) in THF (100 ml) and the reaction mixture
stirred for 20 min. Copper cyanide (3.7 g, 41.2 mmol) was added and
the reaction mixture allowed to warm to between ꢀ45 ꢁC and 38 ꢁC
and stirred for 90 min. The reaction mixture was again cooled to
ꢀ78 ꢁC and 2,3-dibromopropene (4.9 ml, 47.0 mmol) was added.
The reaction mixture was allowed to warm slowly to room tem-
perature, quenched with saturated ammonium chloride solution
(100 ml) and extracted with diethyl ether (2ꢂ100 ml). The com-
bined organic phases were washed with brine, HCl (2 M, 4ꢂ40 ml)
with vigorous shaking, saturated sodium hydrogen carbonate
solution and brine, dried over magnesium sulfate and the solvent
3. Experimental
3.1. General
Reactions were conducted at room temperature under an
atmosphere of nitrogen unless otherwise stated. They were

6530
P.J. Parsons et al. / Tetrahedron 66 (2010) 6526e6533
removed under reduced pressure to give an orange oil. This was
purified using flash column chromatography (24:1 petroleum ether
drops) was added to a solution of 3-(trimethylsilyl)prop-2-ynoic
acid (1.7 g, 12.2 mmol) and oxalyl chloride (1.1 ml, 12.2 mmol) in
DCM (32 ml) and stirred for 30 min. This was added to a solution
of 1-[2-(2-bromoprop-2-en-1-yl)phenyl]-4-(methylamino)but-2-
yn-1-ol hydrochloride (4.2 g, 12.2 mmol) and triethylamine
(4.3 ml, 30.5 mmol) in DCM (48 ml) that had itself been stirring for
10 min. The reaction mixture was stirred for 180 min and
quenched with water (100 ml). The phases were separated and the
organic phase washed with HC1 (1 M, 2ꢂ100 ml), saturated so-
dium hydrogen carbonate solution and brine. The solvent was
removed to give a red oil, which was purified using flash column
chromatography (1:1 diethyl ether/petroleum ether 40/60) to
yield 10 (4.4 g, 86%) as a highly viscous yellow oil. IR (neat) v
(cmꢀ1): 3382, 2962, 2923, 2247, 1744, 1625, 1485, 1441, 1400, 1347,
1252, 1121, 996, 847, 760, 733, 665. dH (300 MHz, CDC13):
7.69e7.66 (m, 1H, Ar), 7.36e7.32 (m, 2H, Ar), 7.27e7.23 (m, 1H, Ar),
5.69e5.65 (d, 1H, J¼11.4 Hz, 10-CH), 5.34e5.44 (d, 2H, J¼29.1 Hz,
1-CH2), 4.48e4.31 (d, 2H, J¼51.8 Hz, 13-CH2), 4.02e3.86 (m, 2H, 3-
CH2), 3.26e3.01 (d, 3H, J¼76.2 Hz, 18-CH3), 2.37 (s, 1H, 19-OH),
0.25e0.24 (d, 9H, J¼3.1 Hz, 17-3CH3). dC (75 MHz, CDC13):
153.6þ153.4 (q, 14-C), 138.4þ138.3 (q.), 134.8 (q), 131.8 (q),
130.8þ130.7 (CH, Ar), 128.9e128.8 (CH, Ar), 127.8e127.7 (CH, Ar),
127.3e127.2 (CH, Ar), 118.5 (CH, 1-C), 98.3 (q, alkyne), 95.4e95.2 (q,
alkyne), 84.3e83.5 (q, alkyne), 80.7e80.5 (q, alkyne), 61.9 (CH, 10-
C), 44.1 (CH2, 3-C), 41.0þ35.5 (CH2, 13-C), 35.7e31.7 (CH3, 18-C).
MS (EI) m/z (rel int.): 418, 402, 338,320, 304, 194, 183, 165, 155,
138, 125, 115, 97, 73, 42. MS (EI) m/z (rel int.): 460, 459, 458, 457,
456, 444, 443, 442, 441, 440. HRMS (ESIþ): calcd for
C20H24BrNO2SiNa, m/z 440.0652, found 440.0639.
€
40/60/diethyl ether) and then with Kugelrohr distillation (0.8 mbar,
90e115 ꢁC) to yield 8 (6.4 g, 73%) as a transparent colourless oil. IR
(neat)v (cmꢀ1):3382, 3069, 3024, 2858, 2742,1698,1629,1599,1576.
dH (300 MHz, CDC13) 10.20 (s,1H,10-CH), 7.87e7.84 (d,1H, J¼7.6 Hz,
Ar), 7.60e7.55 (dt, 1H, J1¼7.5 Hz, J2¼1.4 Hz, Ar), 7.50e7.45 (t, 1H,
J¼7.4 Hz, Ar), 7.38e7.35 (d, 1H, J¼7.5 Hz, Ar), 5.52e5.46 (m, 2H, 1-
CH), 4.21 (s, 2H, 3-CH). dC (75 MHz, CDC13) 192.1 (CH,10-C),138.9 (q),
133.8 (CH, Ar), 132.6 (CH, Ar), 131.6 (CH, Ar), 131.6 (CH, Ar), 131.5 (q),
127.7 (CH, Ar), 118.8 (CH2, 1-C), 43.7 (CH2, 3-C). MS (EI) m/z (rel int.):
225, 208,145,115, 91, 51, 39. HRMS (ESIþ): calcd for C10H9OBrNa, m/z
246.9729, found 246.9723.
3.1.3. tert-Butyl {4-[2-(2-bromoprop-2-en-1-yl)phenyl]-4-hydroxy-
but-2-yn-1-yl}methylcarbamate (9). n-Butyllithium (2.5 M in hex-
anes, 4.8 ml, 12.0 mmol) was added to a cooled (ꢀ95 ꢁC) solution
of tert-butyl methyl(prop-2-yn-1-yl)carbamate (1.9 g, 11.5 mmol)
in THF (200 ml) and stirred for 90 min. 2-(Bromoprop-2-en-1-yl)
benzaldehyde 8 (2.5 g, 11.1 mmol) was added (reaction mixture
<ꢀ95 ꢁC) to the reaction mixture and stirred for 60 min. 2-Bromo-
2-methylpropane (2.0 ml, 17.2 mmol) was added and the reaction
mixture allowed to slowly warm to room temperature. The re-
action mixture was partitioned between water (100 ml) and
diethyl ether (200 ml) and the phases separated. The aqueous
phase was extracted with diethyl ether (50 ml) and the combined
organic phases were washed with brine and dried over magne-
sium sulfate. This was purified using flash column chromatogra-
phy (2:3 diethyl ether/petroleum ether 40/60) to yield 9 (3.4 g,
77%) as a yellow oil. IR (neat) v (cmꢀ1) 3396, 3066, 2977, 2930,
2248, 1679, 1630, 1604, 1581. dH (300 MHz, CDC13): 7.73e7.70 (m,
1H, Ar), 7.35e7.28 (m, 2H, Ar), 7.26e7.23 (m, 1H, Ar), 5.65 (s, 1H, 10-
CH), 5.54 (s, 1H, 1a-CH), 5.44 (s, 1H, 1b-CH), 4.11 (s, 2H, 13-CH2),
4.03e3.87 (m, 2H, 3-CH2), 2.90 (s, 3H, 14-CH3), 1.46 (s, 9H, 17-CH3).
dC (75 MHz, CDC13): 155.2 (q, 15-C), 138.7 (q), 134.7 (q), 131.8 (q),
130.6 (CH, Ar), 128.6 (CH, Ar), 127.6 (CH, Ar), 127.2 (CH, Ar), 118.3
(CH2, 1-C), 83.0 (q, alkyne), 80.2 (q, 16-C), 61.8 (CH, 10-C), 40.0
(CH2, 3-C), 38.2 (CH2 b, 13C), 33.6 (CH3, 14-C), 28.3 (3CH3, 17-C). MS
(EI) m/z (rel int.): 336, 320, 293, 258, 240, 214, 196, 183, 165, 153,
141, 129, 115. HRMS (ESIþ): calcd for C19H24BrO3NNa, m/z
416.0832, found 416.0814.
3.1.6. tert-Butyl{oxybis[4-(2-bromophenyl)but-2-yne-4,1-diyl]}bis
(methylcarbamate) (11). The title compound was tentatively
assigned as the structure of a substance isolated in 6% yield as part
of the synthesis of tert-butyl [4-(2-bromophenyl)-4,4-hydroxybut-
2-yn-1-yl]methylcarbamate 9. dH (300 MHz, CDC13): 7.63e7.61 (d,
2H, J¼7.7 Hz, Ar), 7.50e7.47 (d, 2H, J¼7.8 Hz, Ar), 7.35e7.30 (t, 2H,
J¼7.5 Hz, Ar), 7.15e7.09 (m, 2H, Ar), 5.58e5.54 (m, 1H, 7-CH), 4.68
(br s, 1H, 15-CH), 4.09 (br s, 4H, 10-2CH2), 2.91e2.87 (d, 6H,
J¼10.4 Hz, 11-2CH3) 1.44 (s, 18H, 14-6CH3). dC (75 MHz, CDC13):
142.8 (q, Ar), 132.6 (CH, Ar), 128.8 (CH, Ar), 127.7 (CH, Ar), 127.5 (CH,
Ar),121.2 (q, Ar), 84.0 (q, alkyne), 83.6 (q, alkyne), 80.3 (q,13-C), 71.0
(CH, 7-C), 61.1 (CH2 15-C), 42.5 (CH2, 10-C), 29.7 (CH2, 10-C), 28.4
(CH3, 14-C). It is believed that the missing peaks in the carbon NMR
spectrum may have been lost in the baseline. The spectra are only
temporarily assigned.
3.1.4. 1-[2-(2-Bromoprop-2-en-1-yl)phenyl]-4-(methylamino)but-2-
yn-1-ol hydrochloride (9a). Hydrogen chloride (2 M solution in
ether, 53 ml, 105.2 mmol) was added to tert-butyl{4-[2-(2-bromo-
prop-2-en-1-yl)phenyl]-4-hydroxybut-2-yn-1-yl}methylcarbamate
9 (6.9 g, 17.5 mmol) and the resulting solution stirred for 18 h.
Pentane (50 ml) was added to the reaction mixture and the pre-
cipitate purified by filtration and washing with diethyl ether
(30 ml) and pentane (50 ml). Residual solvent was removed under
reduced pressure to yield 9a (4.7 g, 81%) as an off white solid, mp
96 ꢁC. IR (Nujol) v, (cmꢀ1): 3584, 3297, 3110, 2923, 2855, 2781, 2725,
2441,1808,1731,1633,1570,1462,1440,1413,1401,1378,1296,1212,
1179, 1155, 1116, 1107, 1078, 1017, 969, 961, 903, 884, 867, 764, 655.
dH (300 MHz, DMSO-d6): 9.52 (s, 2H, 14-NH2), 7.65e7.62 (m, 1H, Ar),
7.30e7.27 (m, 2H, Ar), 7.22e7.20 (m, 1H, Ar), 6.28 (br s, 1H, 16-OH),
5.69 (s, 1H, 10-CH), 5.56 (s, 2H, 1-CH2), 4.03e3.82 (m, 4H, 3-CH2-13-
CH2), 2.50 (s, 4H, 15-NCH3-DMSO). dC (75 MHz, DMSO-d6): 139.4
(q), 134.4 (q), 131.8 (q), 129.8 (CH, Ar), 128.0 (CH, Ar), 127.1 (CH, Ar),
127.0 (CH, Ar), 119.3 (CH2, 1-C), 88.6 (q, alkyne), 76.0 (q, alkyne),
59,8 (CH, 10C), 43.1 (CH2, 3-C), 36.8 (CH2, 13-C), 31.3 (CH3, 15-C). MS
(EI) m/z (rel int.): 214, 196, 194, 181, 155, 141, 128, 115, 68, 44. HRMS
(ESþ): calcd for C14H17BrNO, m/z, 294/0488, found 294.0479.
3.1.7. 11-Hydroxy-2-methyl-4-(trimethylsilyl)-1,2,4,5-tetrahydro-
3H-naphtho[2,3,-e]isoindol-3-one (12). Using tributyltin hydride: A
solution of tributyltin hydride (0.15 ml. 0.96 mmol) and AlBN
(spatula end) in benzene (4 ml) was added over 390 min to
a degassed, boiling solution of N-{4-[(2-bromoprop-2-en-1-yl)
phenyl]-4-hydroxybut-2-yn-1-yl}-N-methyl-3-(trimethylsilyl)prop-
2-ynamide 10 (0.40 g, 0.96 mmol) in benzene (50 ml) and stirred
for 30 min. A further solution of tributyltin hydride (0.23 ml,
1.4 mmol) and AlBN (spatula end) in benzene (5 ml) was added to
the boiling reaction mixture over 240 min and the reaction mixture
allowed to cool to room temperature. Solvent was removed under
reduced pressure and the residue purified using flash column
chromatography (gradient; pentane 100% to diethyl ether 100% in
25% increments) to yield 12 (45 mg, 14%) as an off white solid, mp
278e282 ꢁC (decomp.). Using tris(trimethylsilyl)silane: A solution
of tris(trimethylsilyl)silane (0.28 ml, 0.92 mmol), AlBN (spatula
end and N-{4-[(2-bromoprop-2-en-1-yl)phenyl]-4-hydroxybut-2-
yn-1-yl}-N-methyl-3-(trimethylsilyl)prop-2-ynamide 10 (0.35 g,
0.84 mmol) in benzene (20 ml) was degassed and heated to reflux
for 3 days. Solvent was removed under reduced pressure and
3.1.5. N-{4-[2-(2-Bromoprop-2-en-1-yl)phenyl]-4-hydroxybut-2-yn-
1-yl}-N-methyl-3-(trimethylsilyl)prop-2-ynamide (10). DMF (15

P.J. Parsons et al. / Tetrahedron 66 (2010) 6526e6533
6531
residue was purified using flash column chromatography (gradient;
1:3 diethyl ether/pentane to diethyl ether 100%) to yield 12 (62 mg
22%) as an off white solid. Using heat in benzene: A solution of N-
{4-[2-bromoprop-2-en-1-yl)phenyl]-4-hydroxybut-2-yn-1-yl}-N-
methyl-3-(trimethylsilyl)prop-2-ynamide 10 (0.50 g, 1.2 mmol) in
benzene (30 ml) was heated at reflux for 40 h. Solvent was removed
under reduced pressure, hexane added to the residue and the
precipitate purified by filtration and washing with diethyl ether
and hexane to yield 12 (202 mg, 50%). Using heat in toluene: A
solution of N-{4-[2-bromoprop-2-en-1-yl)phenyl]-4-hydroxybut-
2-yn-1-yl}-N-methyl-3-(trimethylsilyl)prop-2-ynamide 10 (0.50 g,
1.2 mmol) and butyl oxirane (2.9 ml, 23.9 mmol) in toluene (10 ml)
was heated at reflux for 3 h. Solvent was removed under reduced
pressure and the residue purified using flash column chromatog-
raphy (gradient; diethyl ether/hexane 1:1. 2:1, 4:1, 1:0, then 1:1
diethyl ether/THF) to yield 12 (207 mg, 76%). IR (Nujol) v, (cmꢀ1):
3043, 2955, 2925, 2868, 2855, 1943, 1921, 1647, 1570, 1501, 1487,
1463, 1442, 1416, 1403, 1371, 1336, 1286, 1247, 1219, 1162, 1147, 1118,
1084, 1028, 905, 868, 854, 835, 747, 721. dH (300 MHz, DMSO-d6):
9.79 (br s, 1H, 19-OH), 8.22e8.19 (d, 1H, J¼8.6 Hz, Ar), 7.74.7.71 (m,
1H, Ar), 7.34e7.41 (m, 2H, Ar), 7.26 (s, 1H, Ar, 6-CH), 4.82e4.35 (dd,
2H, J1¼20.1 Hz, J2¼122.3 Hz, 16-CH2), 3.29e3.22 (m, 2H, 4-CH2),
3.09e2.96 (m, 3H, NeMe), 2.20 (d, 1H, J¼7.3 Hz, 3-CH), ꢀ0.19 (s, 9H,
17-3CH3). dC (75 MHz, DMSO-d6): 169.7 (q, 1-C), 148.3 (q), 141.6 (q),
135.6 (q), 134.2 (q), 133.9 (q), 127.3 (CH, Ar), 126.5 (CH, Ar), 124.8 (q),
124.7 (CH, Ar), 122.2 (CH, Ar, 114.9 (q) 54.7 (CH2, 16-C), 31.1 (CH2, 4-
C), 28.8 (CH3, 18-C), 21.2 (CH, 3-C), ꢀ2.1 (3CH3, 17-C). MS (EI) m/z
(rel int.): 360, 338, 322, 232. HRMS (ESIþ): calcd for C20H23NO2SiNa,
m/z 360.1390, found 360.1388. calcd for C20H24NO2Si, m/z 338.1571,
found 338.1566.
stirred for 30 min. A solution of 2-[3-(trimethylsilyl)prop-2-yn-1-
yl] benzaldehyde 16 (2.50 g, 11.56 mmol) in THF (5 ml) was added
dropwise and the reaction mixture allowed to stir for 60 min. The
reaction was quenched with 2-bromo-2-methylpropane (2.0 ml,
17.33 mmol) and allowed to slowly warm to room temperature. The
reaction mixture was diluted with diethyl ether (2ꢂ150 ml). The
combined organic phases were washed with brine, dried over
magnesium sulfate, filtered and the solvent removed under re-
duced pressure to give a dark orange oil. This was purified using
flash column chromatography (3:2 hexane/diethyl ether) to yield
17 (4.01 g, 90%) as a transparent yellow oil. IR (neat) v (cmꢀ1): 3396,
2963, 2931, 2248, 2177, 1678, 1483, 1455, 1393, 1368, 1251, 1152,
1026, 954, 911, 844, 759, 734. dH (300 MHz, CDC13): 7.66 (m, 1H, Ar),
7.49e7.46 (m, 1H, Ar), 7.34e7.28 (m, 2H, Ar), 5.71 (s, 1H, 10-CH), 4.11
(br s, 2H, 13-CH2), 3.82 (s, 2H, 11e3-CH2), 2.90 (s with long tail, 4H,
14-CH3 and 19-OH), 1.44 (s, 9H, 17.3CH3), 0.17 (s, 9H, 3CH3). dC
(75 MHz, CDC13): 155.2 (q, 15-C), 137.8 (q, Ar), 134.2 (q, Ar), 129.3
(CH, Ar), 127.3 (2CH, 2Ar), 104.2 (q, alkyne), 87.7 (q, alkyne),
82.5e82.2 (q, alkyne), 80.2 (q, 16-C), 62.1 (CH, 10-C), 38.6e37.9
(CH2, br d, 13-C), 33.6 (CH3, 14-C), 28.3 (3CH3, 17-C), 23.5 (CH2, 3-C),
ꢀ0.03 (3CH3, 18-C). MS (EI) I (rel int.): 410, 409, 408, 354, 353, 352,
136. HRMS (ESIþ): calcd for C22H31NO3SiNa, m/z 408.1965, found
408, 1958.
3.1.10. tert-Butyl[4-hydroxy-4-(2-prop-2-yn-1-yl-phenyl)but-2-yn-
1-yl]methylcarbamate (17a). A solution of tert-butyl[4-hydroxy-4-
(2-prop-2-yn-1-yl-phenyl)but-2-yn-1-yl]methylcarbamate
17
(2.53 g, 6.7 mmol) and sodium methoxide (0.11 g, 1.97 mmol) in
DCM (10 ml) and MeOH (10 ml) was stirred at room temperature
for 18 h, diluted with DCM (20 ml), washed with water and the
aqueous fractions extracted with DCM (2ꢂ20 ml). The combined
organic fractions were dried over magnesium sulfate, filtered and,
the solvent removed under reduced pressure to yield 17a (2.04 g,
97%) as a yellow oil. IR (neat) v (cmꢀ1): 3396, 3303, 2977, 2929,
2248, 2120, 1677, 1483, 1455, 1421, 1393, 1368, 1251, 1152, 1050,
1029, 1004, 872, 755. dH (300 MHz, CDC13): 7.66e7.63 (d, 1H,
J¼6.9 Hz, Ar), 7.53e7.51 (d, 1H, J¼6.8 Hz, Ar), 7.36e7.29 (m, 2H, Ar),
5.73e5.71 (d, 1H, J¼4.3 Hz, 10-CH), 4.12 (br s, 2H, 13-CH2), 3.80 (s,
2H, 3-CH2), 2.91 (s, 3H, 14-CH2), 2.46 (br s 1H, 18-OH), 2.23e2.21 (t,
1H, J¼1.4 Hz, 1-CH), 1.45 (s, 9H, 17.3CH3). dC (75 MHz, CDC13): 155.2
(q, 15-C), 137.7 (q. Ar), 134.0 (q, Ar), 129.2 (CH, Ar), 128.7 (CH, 2Ar),
127.2 (CH, Ar), 127.1 (CH, Ar), 82.6 (q, alkyne), 82.2 (q, alkyne), 81.7
(q, alkyne), 80.2 (q, 16-C), 71.1 (CH2, 1-C), 62.1 (CH, 10-C), 38.6e37.9
(CH2, br d, 13-C), 33.6 (CH3, 14-C), 28.3 (3CH2, 17-C), 21.9 (CH2, 3-C).
MS (EI) m/z (rel int.): 336, 330, 280, 112, 101, 58. HRMS (ESIþ): calcd
for C19H23NO3Na, m/z 336.1570, found 336.1552.
3.1.8. 2-[3-(Trimethylsilyl)prop-2-yn-1-yl]benzaldehyde
(16). n-
Butyllithium (8.23 ml, 20.58 mmol) was added dropwise to
a cooled (CO2/acetone) solution of 2-(2-bromophenyl)-1,3-dime-
thylimidazolidine 7 (5.0 g, 19.60 mmol) in THF (100 ml) and the
reaction mixture stirred for 20 min. Copper cyanide (1.84 g,
20.58 mmol) was added and the reaction mixture allowed to
warm to 30 ꢁC and stirred at this temperature for 45 min. The
reaction mixture was again cooled fully and 3-(trimethylsilyl)
propargyl bromide (3.43 ml, 21.56 mmol) added. The reaction
mixture was allowed to warm slowly to room temperature and
quenched with saturated ammonium chloride solution (50 ml).
The reaction mixture was extracted with diethyl ether (2ꢂ150 ml),
the combined organic fractions washed with hydrochloric acid
(2 M, 3ꢂ100 ml with vigorous shaking), saturated sodium hydro-
gen carbonate solution and brine, dried over magnesium sulfate,
filtered and the solvent removed under reduced pressure to give
€
a red oil. This was purified using Kugelrohr distillation (0.09 mbar,
3.1.11. 4-(Methylamino)-1-(2-prop-2-yn-1-yl-phenyl)but-2-1-ol-hy-
140e150 ꢁC) to yield 16 (2.9 g, 69%) as a clear colourless oil. IR
(neat) v (cmꢀ1): 3377, 3071, 2961, 2899, 2834, 2737, 2488, 2343,
2178, 1947, 1695, 1601, 1576, 1487, 1454, 1406, 1320, 1295, 1251,
1198, 1105, 1030, 958, 843, 758, 701, 646. dH (300 MHz, CDC13):
10.21 (s, 1H, 10-CH), 7.82e7.79 (d, 1H, J¼7.6 Hz, Ar), 7.74e7.72 (d,
1H, J¼7.6 Hz, Ar), 7.62e7.57 (m, 1H, Ar), 7.48e7.43 (t, 1H, J¼7.4 Hz,
Ar), 4.11 (s, 2H, 3-CH2), 0.18 (s, 9H, 11-3CH3). dC (75 MHz, CDC13):
192.7 (CH, 10-C), 138.3 (q, Ar), 134.O (CH, Ar), 133.4 (CH, Ar), 133.1
(q, Ar), 129.7 (CH, Ar), 127.2 (CH, Ar), 103.3 (q, alkyne), 88.5 (q,
alkyne), 23.9 (CH2, 3-C), 0.02 (3CH3, 11-C). MS (EI) m/z (rel int.):
239, 217, 102, 79. HRMS (ESIþ): calcd for C13H16OSiNa, m/z
239.0863, found 239.0861.
drochloride (17b). A solution of tert-butyl[4-hydroxy-4-(2-prop-2-
yn-1-yl-phenyl)but-2-yn-1-yl]methylcarbamate
17a
(0.78 g,
2.5 mmol) and hydrochloride acid in diethyl ether (2 M, 2.5 ml,
5.0 mmol) was stirred at room temperature for 3.5 h. Pentane
(7 ml) was added and the precipitate removed by filtration. The
filter cake was washed with diethyl ether and pentane and sucked
dry under nitrogen to yield 17b (0.37 g, 60%) as an off white solid,
mp 96e100 ꢁC. IR (neat) v (cmꢀ1): 3584, 3303, 3246, 2954, 2925,
2855, 2727, 2561, 2490, 2467, 2397, 1602, 1461, 1398, 1377, 1301,
1205, 1116, 1096, 1021, 795, 749. dH (300 MHz, DMSO-d6): 9.48 (br s,
2H, NH2), 7.62e7.60 (d, 1H, J¼6.3 Hz, Ar), 7.50.7.48 (d, 1H, J¼6.5 Hz,
Ar), 7.34e7.28 (m, 2H, Ar), 6.28 (br s, 1H, 16-OH), 5.65 (s, 1H, 10-CH),
3.91 (s, 2H, 13-CH2), 3.90 (s, 2H, 3-CH3), 3.15 (s, 1H, 1-CH), 2.52 (s,
3H,14-CH3). dC (75 MHz, DMSO-d6): 138.5 (q, Ar),133.7 (q, Ar),128.4
(CH, Ar), 128.0 (CH, Ar), 126.7 (2CH, 2Ar), 88.2 (q, alkyne), 81.8 (CH,
1-C), 78.0 (q, alkyne), 73.9 (q, alkyne), 59.9 (CH, 10-C), 36.8 (CH2, 13-
C), 31.3 (CH3, 14-C), 21.0 (CH2, 3-C). MS (EI) m/z (rel int.): 213, 194,
181, 165, 153, 141, 128, 115, 103, 94, 77, 68, 44. MS (EI) m/z (rel int.):
3.1.9. tert-Butyl(4-hydroxy-4-{2-[3-(trimethylsilyl)prop-2-yn-1-yl]
phenyl}but-2-yn-1-yl)methylcarbamate
(17). n-Butyllithium
(5.1 ml, 12.71 ml) was added (reaction mixture <ꢀ90 ꢁC through-
out) to a cooled (N2/methanol) solution of tert-butyl methyl(prop-
2-yn-1-yl)carbamate (2.15 g, 12.7 mmol) in THF (200 ml) and

6532
P.J. Parsons et al. / Tetrahedron 66 (2010) 6526e6533
236, 214, 213, 181, 165, 136, 100, 71. HRMS (ESIþ): calcd for
C14H16NO, m/z 214.1226, found 214.1217.
(75 MHz, CDCl3): 199.3 (q, 10-C), 171.7 (q, 14-C), 137.1 (q), 136.6 (q),
136.6 (q),136.0 (q),132.5 (CH, Ar),130.6 (CH, Ar),128.8 (CH, Ar),127.1
(CH, Ar), 81.8 (q, 2-C), 71.0 (CH, 1-C), 54.9 (CH2, 11-C), 40.5 (CH2, 16-
C), 29.3 (CH3, 17-C), 23.6 (CH2, 3-C), 14.7 (CH2, 15-C), 1.1 (CH3, 18-C).
MS (EI) m/z (rel int.): 413, 363, 274, 234, 218, 121, 101. HRMS (ESIþ):
calcd for C20H25NO2SiNa, m/z 362.1547, found 362.1533.
3.1.12. N-[4-Hydroxy-4-(2-prop-2-yn-1-yl-phenyl)but-2-yn-1-yl]-N-
methyl-3-(trimethylsilyl)prop-2-ynamide (18). Acid chloride method
from amine salt 17b: DMF (five drops) was added to a solution of 3-
(trimethylsilyl)prop-2-ynoic acid (196 mg, 1.38 mmol) and oxalyl
chloride (0.13 ml,1.38 mmol) in DCM (3 ml) and the solution stirred
at room temperature for 40 min. This was then added dropwise to
a solution of 4-(methylamino)-1-(2-prop-2-yn-1-yl-phenyl)but-2-
yn-1-ol-hydrochloride 17b (327 mg, 1.31 mmol) and triethylamine
(0.46 ml, 3.27 mmol) in DCM (4 ml) that had itself been stirring for
20 min. The reaction mixture was stirred at room temperature for
20 min and quenched with water. The phases were separated, the
organic phase was washed with hydrochloric acid (2 M, 2ꢂ10 ml),
saturated sodium hydrogen carbonate solution and brine, dried
over magnesium sulfate, filtered and the solvent removed under
reduced pressure to give a red oil. This was purified using flash
column chromatography (2:3 hexane/diethyl ether) to yield 18
(279 mg, 63%) as a viscous yellow oil. Hydrogen iodide method from
carbamate 17a: DMF (five drops) was added to a solution of 3-
(trimethylsilyl)prop-2-ynoic acid (1.82 g, 12.76 mmol) and oxalyl
chloride (1.1 ml, 12.76 mmol) in MeCN (8 ml) and the solution
stirred at room temperature for 30 min. This was added to a cooled
(ice/water) solution of tert-butyl {4-hydroxy-4-(2-prop-2-yn-1-yl-
phenyl)but-2-yn-1-yl]methylcarbamate (1.00 g, 3.19 mmol) and
sodium iodide (0.96 ml, 6.38 mmol) and the reaction mixture was
stirred at room temperature for 10 min. Triethylamine (1.8 ml,
12.76 mmol) was added and the reaction mixture stirred for a fur-
ther 30 min. The reaction mixture was quenched with hydrochloric
acid (1 M, 25 ml), extracted with diethyl ether (1ꢂ100 ml,
2ꢂ50 ml), the combined organic fractions were washed with sat-
urated sodium hydrogen carbonate solution and brine, dried over
magnesium sulfate, filtered and the solvent removed to give a red
oil. This was purified using flash column chromatography (1:1
pentane/diethyl ether) to yield 18 (301 mg, 28%) as a dark red oil. IR
(neat) v (cmꢀ1): 3378, 3306, 2961, 2924, 2853, 2247, 2119, 1716,
1627, 1485, 1455, 1400, 1348, 1253, 1124, 997, 911, 848, 761, 734. dH
(300 MHz, CDCl3): 7.63e7.60 (m, 1H, Ar), 7.53e7.50 (m, 1H, Ar),
7.34e7.29 (m, 2H, Ar), 5.74e5.70 (d, 1H, J¼12.9 Hz, 10-CH),
4.48e4.30 (dd, 2H, J1¼1.5 Hz, J2¼52.6 Hz, 13-CH2), 3.79e3.77 (t, 2H,
J¼2.7 Hz, 3-CH2), 3.25e3.00 (d, 3H, J¼75.6 Hz, 18-CH3), 2.23e2.20
(m, 1H, 1-CH), 0.24e0.23 (d, 9H, J¼2.8 Hz, 3-CH3). dC (75 MHz,
CDCl3): 153.6e153.4 (q, 14-C), 137.14e136.36 (q, Ar), 134.0 (q, Ar),
129.5e29.4 (CH, Ar), 129.5e129.4 (CH, 2Ar), 129.0e128.9 (CH, Ar),
127.2e127.1 (CH, Ar), 98.35e95.4 (q, alkyne), 84.0e83.3 (q, alkyne),
81.7e81.6 (q, alkyne), 80.7e80.5 (q, alkyne), 71.1 (CH,1-C), 62.1 (CH,
10-C), 41.0e35.5 (CH2, 13-C), 35.7e31.7 (CH3, 18-C), 22.0 (CH2, 3-C),
ꢀ07 (3CH3, 17-C), MS (EI) m/z (rel int.): 725, 697, 530, 461, 360, 330,
242, 120. HRMS (ESIþ): calcd for C20H23NO2SiNa, m/z 360.1390,
found 360.1373.
3.1.14. N-{4-[2-(2-Bromoprop-2-en-1-yl)phenyl]-4-oxobut-2-yn-1-
yl}-N-methyl-3-(trimethylsilyl)prop-2-ynamide (24). A mixture of
N-{4-[2-(2-Bromoprop-2-en-1-yl)phenyl]-4-hydroxybut-2-yn-1-
yl}-N-methyl-3-(trimethylsilyl)prop-2-ynamide
10
(100 mg,
0.24 mmol) and manganese dioxide (438 mg, 5.04 mmol) in DCM
was stirred at room temperature for 48 h. The reaction mixture was
briefly stirred with magnesium sulfate and then filtered through
Celite. The solvent was removed under reduced pressure to yield 24
(97 mg, 97%) as a viscous yellow oil. IR (neat) v (cmꢀ1): 3278, 2961,
2925, 2230, 1639, 1572, 1484, 11396, 1251, 1128, 902, 849, 761, 735.
dH (300 MHz, CDC13): 8.21e8.17 (m, 1H, Ar), 7.60e7.52 (m, 1H, Ar),
7.46e7.41 (t, 1H, J¼7.6 Hz, Ar), 7.40e7.35 (t, 1H, J¼6.9 Hz, Ar),
5.48e5.44 (m, 2H, 1-CH2), 4.67e4.51 (d, 2H, J¼49.7 Hz, 13-CH2),
4.20e4.19 (d, 2H, J¼3.9 Hz, 3-CH2), 3.33e3.09 (d, 3H, J¼72.5 Hz 18-
CH3), 0.25e0.24 (d, 9H, J¼2.5 Hz 17-3CH3). dC (75 MHz, CDC13):
178.5e178.3 (q, 10-C), 153.7e153.4 (q, 14-C), 138.9þ138.7 (q),
134.9e134.8 (q), 133.7e133.6 (CH, Ar), 133.5e133.4 (CH, Ar),
132.0e131.9 (CH, Ar), 131.51e31.45 (q), 127.3 (CH, Ar),
118.52þ118.45 (CH2, 1-C), 99.02e98.96 (q, alkyne), 95.1e94.9 (q,
alkyne), 87.2e86.7 (q, alkyne), 83.6e83.0 (q, alkyne), 44.9 (CH2, 13-
C), 41.0þ35.6 (CH2, 13-C), 35.9e32.1 (CH3, 18-C), ꢀ0.8 (3CH3, 17-C).
MS (EI) m/z (rel int.): 442, 441, 440, 439, 438, 285, 146, 145. HRMS
(ESIþ): calcd for C20H22BrNO2SiNa, m/z 438.0495, found 438.0486.
3.1.15. 4-{[2-(2-Bromoprop-2-en-1-yl)phenyl]ethynyl}-1-methyl-
1,5-dihydro-2H-pyrrol-2-one (25). A solution of N-{4-[2-(2-Bro-
moprop-2-en-1-yl)phenyl-4-oxobut-2-yn-1-yl}-N-methyl-3-(tri-
methylsilyl)prop-2-ynamide 24 (210 mg, 0.50 mmol) and butyl
oxirane (1.2 ml,10.09 mmol) in toluene (10 ml) was heated at reflux
for 6 h. Solvent was removed under reduced pressure and the
residue purified using flash column chromatography (1:1 diethyl
ether/hexane) to yield 25 as a pale yellow oil (47 mg, 30%). IR (neat)
v (cmꢀ1): 3432, 3067, 2954, 2923, 2853, 2240, 2206, 1682, 1629,
1483, 1447, 1394, 1328, 1287, 1259, 1189, 1109, 1016, 909, 892, 856,
760, 732. dH (300 MHz, CDC13): 7.51e7.48 (d, 1H, J¼7.7 Hz, Ar),
7.40e7.34 (m, 1H, Ar), 7.314e7.308 (d, 1H, J¼1.7 Hz, Ar), 7.29e7.28
(m, 1H, Ar), 6.35 (s, 1H, 13-CH), 5.51 (s, 1H, 1-CH2), 5.451e5.446 (d,
1H, J¼1.5 Hz, 1-CH2), 4.09 (s, 2H, 15-CH2), 3.91 (s, 2H, 3-CH2), 3.05
(s, 3H, 16-CH3). dC (75 MHz, CDC13): 170.7 (q, 14-C), 139.4 (q), 136.4
(q), 132.5 (CH, Ar), 131.0 (q), 130.3 (CH, 13-C), 129.7 (2CH, 2Ar), 127.2
(CH, Ar), 121.9 (q), 118.3 (CH2, 1-C), 97.9 (q, alkyne), 85.7 (q, alkyne),
56.8 (CH2, 15-C), 46.0 (CH2, 3-C), 29.0 (CH3, 16-C). MS (EI) m/z (rel
int.): 340, 338, 274, 218, 113, 112, 101. HRMS (ESIþ): calcd for
C16H14BrNONa, m/z 338.0151, found 338.0129.
3.1.13. 1-Methyl-4-[2-oxo-2-(2-prop-2-yn-1-yl-phenyl)ethyl]-3-
[(trimethylsilyl)methyl]-1,5-dihydro-2H-pyrrol-2-one (19). A solu-
tion of N-[hydroxyl-4-(2-prop-2-yn-1-yl-phenyl)but-2-yn-1-yl]-N-
methyl-3-(trimethylsilyl)prop-2-ynamide 18 (293 mg, 0.87 mmol)
in toluene was heated at reflux for 4 h and the solvent removed
under reduced pressure. The mixture was stirred at room temper-
ature for 20 min and quenched with water. The residue was purified
using flash column chromatography (24:1 diethyl ether/hexane) to
yield 19 as a clear oil (27 mg, 9%). IR (neat) v (cmꢀ1): 3307, 2954,
2926, 2239, 1681, 1450, 1421, 1399, 1249, 1164, 1073, 987, 910, 842,
734. dH (300 MHz, CDCl3): 7.73e7.69 (m, 2H, Ar), 7.55e7.50 (m, 1H,
Ar), 7.41e7.36 (m, 1H, Ar), 3.95 (s, 2H, 16-CH2), 3.91 (s, 2H, 11-CH2),
3.89e3.88 (d, 2H, J¼2.6 Hz, 3-CH2), 3.02 (s, 3H,17-CH3), 2.18e2.16 (t,
1H, J¼2.7 Hz, 1-CH), 1,77 (s, 2H, 15-CH2), 0.02 (s, 9H, 18-3CH3). dC
3.1.16. (4-Hydroxy-but-2-ynyl)-methyl-carbamic acid tert-butyl
ester (30). To N-Boc-N-methylpropargylamine 29 (1.32 g, 7.81
mmol, 1.0 equiv) in THF (40 ml) at ꢀ78 ꢁC was added n-butyl-
lithium in hexanes (3.91 ml, 2.3 M, 8.80 mmol, 1.1 equiv). The
solution was stirred for 30 min. Powdered para-formaldehyde-d2
(500 mg, 15.6 mmol, 2.0 equiv) was added in one portion. The
solution was allowed to warm to room temperature over 1 h upon
which water and CH2Cl2 were added. The layers were separated
and the aqueous layer was extracted over magnesium sulfate and
concentrated under reduced pressure. Purification by flash column
chromatography (10% diethyl ether in hexanes) gave the title
compound 30 as a light yellow oil (1.49 g, 95%). IR (neat) v (cmꢀ1):
3427, 2977, 2933, 2202, 2096, 1691. dH (300 MHz, CDC13): 4.01 (br s,
2H, 4-CH2), 2.90 (br s, 1H, OH), 2.86 (s, 3H, 5-NMe), 1.42 (s, 9H, 8-

P.J. Parsons et al. / Tetrahedron 66 (2010) 6526e6533
6533
CH3). dC (75 MHz, CDC13): 155.7 (6-CO), 82.4 (C), 81.0 (C), 80.6 (C),
38.5 (4-CH2), 33.9 (5-CH3), 28.7 (8-CH3). HRMS (ESIþ): calcd for
C10H15D2NO3Na: m/z 224.1226, found 224.1227.
2237, 1676, 1630. dH (300 MHz, CDC13): 4.58e4.66 (dd, 1H, J1¼8.85,
J2¼8.85 Hz, 2a-CH2), 3.84e4.02 (m, 2H, 6-CH2), 3.69e3.78 (dd, 1H,
J1¼8.67, J2¼12.62 Hz, 2b-CH2), 3.20e3.38 (m, 1H, 1-CH), 2.98 (s, 3H,
7-NMe), 2.09e2.21 (dd, 1H, J1¼4.14, J2¼12.43 Hz, 11a-CH2),
1.53e1.65 (dd, 1H, J1¼12.53, J2¼12.53 Hz, 11b-CH2), 0.04 (s, 9H, 12-
SiMe3). dC (75 MHz, CDC13): 171.3 (8-CO), 136.2 (C), 132.7 (C), 76.9
(2-CH2), 51.6 (6-CH2), 40.7 (1-CH), 29.4 (7-NMe), 28.9 (11-CH2),
ꢀ1.0 (12-SiMe3). HRMS (ESIþ): calcd for C14H19D2NO2Na: m/z
288.1359, found 288.1352.
3.1.17. (4-Allyloxy-but-2-ynyl)-methyl-carbamic acid tert-butyl ester
(31). To a solution of NaH (60%, 286 mg, 7.16 mmol, 1.3 equiv) in THF
was added dropwise D2 propargylic alcohol 30 (1.11 g, 5.51 mmol,
1.0 equiv). The solution was stirred for 1 h after which time allyl
bromide (666 mg, 0.48 ml, 5.51 mmol,1.0 equiv) was added dropwise
over 5 min at 0 ꢁC. The solution was allowed to warm to room tem-
perature over 2 h and was added to a stirring biphasic mixture of 10%
aqueous K2CO3 solution and diethyl ether. The layers were then
separated, the organic layer was washed with water and brine, dried
over magnesium sulfate and concentrated under reduced pressure.
Purification by flash column chromatography (10% diethyl ether in
hexanes) to yield 31 (1.24 g, 93%) as a pale yellow oil. IR (neat) v
(cmꢀ1): 2929, 2249, 2084, 1695, 1455, 1247. dH (300 MHz, CDC13):
5.80e5.97 (m,1H, 2-CH), 5.14e5.34 (m, 2H,1-CH2), 3.94e4.06 (m, 4H,
3,7-CH2), 2.89(s, 3H, 8-NMe),1.45(s, 9H,11-CH3). dH (75 MHz, CDC13):
155.2 (9-CO), 133.9 (2-CH), 117.8 (1-CH2), 81.7 (C), 80.0 (C), 79.2 (C),
70.5 (3-CH2), 38.6 (7-CH2), 33.4 (8-NMe), 28.3 (11-CH3). HRMS (ESIþ):
calcd for C13H19D2NO3Na: m/z 264.1539, found 264.1539.
Acknowledgements
We thank the EPSRC, GlaxoSmithKline and Pfizer Pharmaceu-
ticals for funding this work and Drs Daryl Waters, Florian Waken-
hut and Clive Penkett for useful discussions. The award of Professor
Parsons fellowships to L.P. and D.F. is noted.
Supplementary data
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2010.05.051.
3.1.18. 3-Trimethylsilanyl-propynoic acid (4-allyloxy-but-2-ynyl)-
methyl-amide ester (32). To a solution of D2 (4-allyloxy-but-2-
ynyl)-methyl-carbamic acid tert-butyl ester 31 (917 mg, 3.80 mmol,
1.0 equiv) in CH2Cl2 (30 ml) was added TFA (2.17 g, 1.41 ml,
19.0 mmol, 5.0 equiv) dropwise over 5 min. The solution was
allowed to stir for a further 15 h and the reaction mixture was
concentrated under reduced pressure to yield the amine TFA salt as
a dark oil, which was used without further purification. To the
amine salt was added CH2Cl2 (7 ml) followed by a dropwise addi-
tion of triethylamine (1.23 g, 1.69 ml, 12.2 mmol, 3.2 equiv) over
10 min under a flow of nitrogen at 0 ꢁC. To the solution was then
added freshly prepared trimethylsilylpropynoyl chloride
(3.80 mmol, 1.0 equiv) in CH2Cl2 (7 ml) dropwise and stirred for
a further 30 min, after which time the reaction was washed with
1 M HCl solution, saturated aqueous Na2CO3 solution, water and
brine, dried over magnesium sulfate and concentrated under re-
duced pressure. The yellow oil was then purified by flash column
chromatography (20% diethyl ether in hexanes) to yield 32 as a light
yellow oil (d, 343 mg, 34%). IR (neat) v (cmꢀ1): 2962, 2923, 2164,
2089, 1638, 1398, 848. dH (300 MHz, CDC13): 5.81e5.98 (m, 1H, 2-
CH), 5.17e5.35 (m, 2H, 1-CH2), 4.22e4.46 (m, 2H, 7-CH2), 3.99e4.04
(m, 2H, 3-CH2), 23.26 (s, 1.5H, 8-NMe), 3.01 (s, 1.5H, 8-NMe), 24 (s,
9H,12-SiMe3). dC (75 MHz, CDC13): 154.2 (9-CO),133.7 (2-CH),118.0
(1-CH2,), 98.0 (C), 95.5 (C), 79.9 (C), 70.6 (3-CH2), 40.8 (35.5, 7-CH2),
35.4 (31.5, 8-NMe), ꢀ0.8 (112-SiMe3). HRMS (ESIþ): calcd for
C14H19D2NO2Na: m/z 288.1359, found 288.1358.
References and notes
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3.1.19. 7-Methyl-5-trimethylsilanyl-3,3a,4,5,7,8-hexahydro-furo-
[3,4-e]isoindol-6-one (33). D2 3-Trimethylsilanyl-propynoic acid (4-
allyloxy-but-2-ynyl)-methyl-amide 32 (200 mg, 0.75 mmol,
1.0 equiv) in toluene (10 ml) was heated at reflux for 3.5 h. The
reaction mixture was concentrated under reduced pressure to yield
33 (198 mg, 99%) as a colourless oil. IR (neat) v (cmꢀ1): 3449, 2952,