A highly diastereoselective series of Nicholas cyclisation reactions of N-Boc-protected propargylamines

Article abstract of DOI:10.1016/j.tet.2012.08.087

The reaction of N-Boc-protected propargylamine with salicylaldehyde derivatives and their subsequent Nicholas cyclisation reaction to provide a range of novel benzopyrans is reported. The cyclisation reactions proceeded with excellent levels of diastereos

Full text of DOI:10.1016/j.tet.2012.08.087

Tetrahedron 68 (2012) 10040e10048
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Tetrahedron
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A highly diastereoselective series of Nicholas cyclisation reactions
of N-Boc-protected propargylamines
,
a
a,
Peter Brawn a, Elizabeth Tyrrell a , Mark Carew , Kibur Hunie Tesfa y, Iain Greenwood b
*
a School of Pharmacy & Chemistry, Kingston University, Penrhyn Road, Kingston Upon Thames, Surrey KT1 2EE, UK
b St George’s, University of London, Cranmer Terrace, London SW17 ORE, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 May 2012
Received in revised form 6 August 2012
Accepted 28 August 2012
Available online 10 September 2012
The reaction of N-Boc-protected propargylamine with salicylaldehyde derivatives and their subsequent
Nicholas cyclisation reaction to provide a range of novel benzopyrans is reported. The cyclisation re-
actions proceeded with excellent levels of diastereoselectivity to afford compounds with cis-relative
stereochemistry. As far as we are able to ascertain these are the first reported examples of Nicholas
cyclisation reactions of propargyl alcohols that bear a terminal alkynyl N-protected amino motif.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
Ph
Ph
In a previous paper we described the antihypertensive activity
of a range of novel benzopyrans1 that were synthesized using
a variation of an intramolecular Nicholas reaction2 that was de-
veloped in our laboratories.3 The key ring closure occurs by the
reaction of a tri-substituted alkenyl moiety, the nucleophile, with
a dicobalt hexacarbonyl-stabilised ‘Nicholas’ cation.4 We also
demonstrated that the reaction sequence that consists of cobalt
complexation of the alkynyl moiety, intramolecular cyclisation and
finally the oxidative decomplexation of dicobalt hexacarbonyl
could be conveniently achieved in a one-pot process.5 The com-
pounds from this series of reactions are interesting from the point
of view that they contain several of the key pharmacophores
present in the benchmark antihypertensive agent cromakalim (1).
Results obtained from a series of in vitro studies6 suggested that
despite the simplicity of our analogues they nevertheless exhibited
antihypertensive activity albeit by a cellular mechanism other than
potassium channel activation. From an array of novel benzopyrans
screened the aryl monofluorinated compounds (2a) and (2b)
proved to be the most potent (Fig. 1).
O
N
F
F
F
F
NC
OH
O
O
O
1
2a
2b
Fig. 1. Cromakalim 1 and novel benzopyrans 2a and 2b.
modification was twofold. The resulting benzopyrans would con-
tain a propargylic amide moiety, which may confer interesting
in vitro binding properties. Secondly most examples7 of the Nich-
olas reaction involve a propargyl alcohol/ether that bears a terminal
R group (R¼H, CH3, aryl), such as the substrate (3) employed on our
previous studies. In this study we were keen to break with tradition
in the use of an N-protected propargylamine moiety (4) and hence
provide diversity in this chemistry (Fig. 2).
The chemistry of related ynamines has been the subject of
a review8 and the corresponding cobalt complexes have mainly
been utilized in the PausoneKhand reaction.9 As far as we have
been able to ascertain, however, the use of propargylamines in
Nicholas chemistry is minimal10 and we have been unable to re-
trieve an example. This modification would thus represent an im-
portant novel variation to existing Nicholas-style chemistry as well
as provide benzopyrans with a propargylic amide bond. This is an
important development as it facilitates the incorporation of han-
dles, such as small peptides, for potential drug delivery purposes.
Furthermore if the ynamino moiety is derived from an optically
pure source, such as an amino acid, we have the potential means of
controlling the stereochemistry of the subsequent ring closure. In
Encouraged by these results we directed our attention towards
the synthesis of a more diverse range of benzopyrans containing
both monofluorinated and difluorinated aryl substituents for fur-
ther screening purposes. In order to introduce additional structural
diversity into this range of benzopyrans we focused upon changes
to the terminal alkynyl substituent. Our rationale for this
* Corresponding author. Tel.: þ44 208 547 8819; fax: þ44 208 547 7562; e-mail
address: e.tyrrell@kingston.ac.uk (E. Tyrrell).
y
In part.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.08.087

P. Brawn et al. / Tetrahedron 68 (2012) 10040e10048
10041
deprotonation of N-Boc-propargylamine11 including n-BuLi, soda-
mide and LiHMDS before settling on LDA (2 equiv in THF). The re-
action of the subsequent alkynide anion proved, however, to be
more of a challenge providing the propargyl alcohols 4aei in
modest to good yields. The alkynylation reaction appears to be
sensitive to both the presence of an N-Boc-amino substituent as
well as the substitution pattern of the aryl ring. With regard to the
influence of the amino moiety on the efficiency of the alkynylation
step consider the three highest yielding alkynylations in Table 1:
entry 1 4a (56%), entry 2 4b (45%) and entry 3 4c (55%). A com-
parison of these data, with those for the corresponding phenyl-
ethynyl alkynylations, give the following (84%), (82%) and (70%),
respectively. With regard to the aryl substituents it seems that the
aryl substitution pattern influences the electrophilic nature of the
carbonyl to a greater degree than the actual number of aryl
electron-withdrawing substituents present. Thus the presence of
two fluorine substituents, entry 8 (54%), does not significantly re-
duce the reactivity of the carbonyl compared to an absence of
fluorine, entry 1 (56%). On the other hand the relative position, of
the aryl substituents, does have an impact. For example compare
entry 8 (54%) with entry 4 (35%), entry 5 (37%) or entry 6 (34%).
With regard to monofluorination the effects are even more marked
compare entry 2 (45%) or entry 3 (55%) with entry 7 (28%) and entry
9 (>5%).
BocHN
R1
R
O
R1
R2
R3
R2
R3
OH
CH3
CH3
OH
CH3
CH3
O
R4
R4
3
4
Fig. 2. Cyclisation precursors.
this paper we wish to disclose the results from the synthesis and
cyclisation of novel compounds based upon compound (4). In
particular we were keen to determine whether the presence of
a terminal N-Boc-amino substituent might exert an influence upon
either the efficiency and/or the selectivity of the subsequent cyc-
lisation reactions.
2. Results and discussion
Conversion of the propargyl alcohols 4aeh into their corre-
sponding hexacarbonyl dicobalt complexes, 6aeh (Scheme 2) oc-
curred in good to excellent yields. The intramolecular Nicholas
cyclisation reaction was carried out by exposure of a dichloro-
methane solution of the complexed propargyl alcohol, maintained
at 0 ꢀC, to a Lewis acid. This reaction, to afford 7aeh, was re-
markably facile taking place within the time it takes to carry out
a TLC analysis of the reaction mixture. This process is facilitated by
the intense red colour of the complex, which makes the product
distribution readily visible by TLC analysis. In addition the com-
plexation of alkynes, akin to 7aeh, helps in the discrimination of
diastereoisomers by facilitating differentiation12 in chromatogra-
phy retention times for instance. Although a number of decom-
plexing agents have been used13 we have found that for this
particular system the oxidative decomplexation of dicobalt hex-
acarbonyl using ceric ammonium nitrate (CAN) was the reagent of
choice. This provided benzopyrans 8aeh in good to excellent yields
(Scheme 2).
Our method of accessing propargyl alcohols 6aei is shown
(Scheme 1) and the results tabulated (Table 1).
R1
O
O
R1
O
i. K2CO3
R2
R3
R2
R3
CH3
CH3
H
CH
H
3
ii
Br
CH
3
OH
R4
R4
5 a-i
BocHN
R1
R2
R3
i. LDA
OH
CH3
CH3
NHBoc
ii.
O
HC
R4
BocHN
R1
BocHN
R1
4a-i
Co2(CO)6
Co2(CO)6
CH3
Scheme 1.
R2
R3
R2
R3
BF3.OEt2
Co2CO8
DCM
OH
CH3
CH3
F
Table 1
The isolated yields for the syntheses of novel benzopyrans 8aeh
O
CH3
O
R4
R4
Entry
Substituent
5a (%)
4 (%)
6 (%)
7 (%)
8 (%)
a. R1e4¼H
86
99
91
95
91
92
23
79
95
56
45
55
35
37
34
28
54
<5
79
71
84
76
55
67
53
67
d
94
62
58
95
76
39
92
71
d
79
97
76
96
73
91
98
52
d
6a-h
7a-h
1
2
3
4
5
6
7
8
9
b. R2¼F
c. R4¼F
BocHN
d. R1, R2¼F
e. R1, R4¼F
f. R2, R3¼F
g. R3¼F
R1
H
CH3
CH3
h. R2, R4¼F
H
R2
R3
i. R1¼F
CAN
F
a
Isolated yields.
O
R4
The data in Table 1 reveal some interesting trends; although the
initial O-alkenylation was an efficient and high yielding reaction
the subsequent alkynylation step proved to be a more capricious
transformation. Initially we examined a number of bases for the
8a-h
Scheme 2.

10042
P. Brawn et al. / Tetrahedron 68 (2012) 10040e10048
In the synthetic sequence the alkynylation step proved to be
The corresponding 19F NMR spectrum of compound 8h is shown
(Fig. 5) and serves to confirm the presence of only one di-
astereoisomer. The second fluorine resonance at ꢁ139.7 ppm results
from an incorporation of a fluoride ion derived from the Lewis acid.
the limiting transformation however the three steps consisting
of complexation, cyclisation and decomplexation proved to be
highly efficient ranging from 24% overall yield (entry 6) to 69%
(entry 4). As the hexacarbonyl dicobalt complexes are highly
coloured (red) we have found it convenient, and more efficient,
to carry out the complexation, cyclisation and decomplexation
steps in one-pot by simply monitoring each step by TLC
analysis.
Analysis of the resulting benzopyrans 8aeh confirmed that the
key Nicholas cyclisation reaction had taken place with excellent
levels of diastereoselectivity. The 1H NMR spectrum for compound
8h, for instance, showed that the benzylic proton, which was res-
PBRX228_19F-3.jdf
0.15
0.10
M02(dd)
0.05
onant at
d 3.9 ppm, overlapped with the resonance attributed to
M01(m)
the methylene CH2 derived from the propargyl group (Fig. 3A).
When the NMR sample was run in acetone-d6, from CDCl3, the
overlapping signals separated into two resonances. The first
0
appeared as a broad singlet at
d 3.85 ppm attributed to CH2 and the
1.37
1.00
second resonance at 3.89 ppm attributed to the benzylic proton.
d
-135.0
-135.5
-136.0
Chemical Shift (ppm)
-136.5
-137.0
This appeared as a broadened doublet with a coupling constant J
4.0 Hz (Fig. 3B).
Fig. 5. Fluorine NMR spectrum of compound 8h.
A
B
Fig. 3. Part of the 1H NMR spectrum of 8h.
With the information obtained in Fig. 3B, i.e., the precise
chemical shift of the benzylic proton in acetone-d6, we were then
3. Conclusion
d
able to confirm the relative stereochemistry of the two adjacent
protons by carrying out a NOESY experiment in acetone-d6. The
spectrum obtained is shown (Fig. 4). This clearly shows an in-
teraction between the benzylic proton and the adjacent methine
Although we anticipated that the presence of the terminal N-
Boc-protected propargylamine would not impede the subsequent
Nicholas cyclisation it was nevertheless gratifying to establish that
both the efficiency of the cyclisation reactions and the corre-
sponding diastereoselectivity of the Nicholas cyclisations remained
consistent. The benzopyrans that resulted from this novel modifi-
cation to the Nicholas reaction will now be screened for their an-
tihypertensive activity and the results will be disseminated in due
course. In addition it is our intention to extend this study to include
the use of chiral N-Boc-protected propargylamines. As cobalt
complexes such as 6aeh are known to exhibit more sp2 character
a chiral complex should adopt a non-linear geometry and thus fa-
cilitate stereocontrol over the subsequent cyclisation reaction.
hydrogen atom, which resonates at d 2.4 ppm. The information that
we obtained from these experiments, based upon the magnitude of
the coupling constant J, for the benzylic proton, as well as the re-
sults obtained from the NOESY NMR experiments, suggested that
the two newly generated stereocentres, resulting from the Nicholas
reaction, have a cis-stereochemical relationship.
0
2
4
6
8
4. Experimental14
4.1. Physical measurements and materials
8
7
6
5
4
3
2
1
0
Melting point determinations were recorded using a Stuart
Scientific SMP3 digital melting point apparatus and are un-
corrected. IR spectra were recorded on a PerkineElmer 1600 series
F2 Chemical Shift (ppm)
Fig. 4. NOESY 1H NMR spectrum of 8h. The relevant protons are circled.

P. Brawn et al. / Tetrahedron 68 (2012) 10040e10048
10043
FTIR spectrophotometer and were calibrated using a standard
polystyrene film. The spectra were recorded either as thin films for
liquids, between sodium chloride discs or for solids as a Nujol mull.
All infrared data are quoted in wave numbers (cmꢁ1). Proton nu-
clear magnetic resonance spectra (1H NMR) were recorded at
400 MHz using a JEOL Eclipse 400 MHz spectrometer. Peak posi-
petroleum ether): vmax (NaCl)/cmꢁ1 (thin film) 2866, 1690, 1606,
1478, 1380, 1262, 1216, 1068; 1H NMR (400 MHz, CDCl3):
d
¼10.36
(1H, d, J¼0.9 Hz, COeH), 7.61e7.56 (1H, m, AreH), 7.31 (1H, ddd,
J¼1.6, 8.1, 11.4 Hz, HeAr), 7.09 (1H, ddd, J¼0.6, 4.5, 8.1 Hz, HeAr),
5.51e5.46 (1H, m, HeC]C); 4.73 (2H, d, J¼7.5 Hz, CH2); 1.74 (3H, s,
CH3); 1.63 (3H, s, CH3); 13C NMR (100 MHz, CDCl3):
d
¼189.4 (d,
tions are quoted using the
d
scale relative to tetramethylsilane
3JCeF¼3.1 Hz), 156.9 (d, JCeF¼248.29 Hz), 154.5, 149.4 (d,
4
(d
¼0) as an internal standard. Carbon-13 NMR spectra (13C NMR)
3JCeF¼10.7 Hz), 141.1, 123.7 (JCeF¼7.7 Hz) 123.1 (d, JCeF¼3.0 Hz),
were recorded at 100 MHz on a JEOL Eclipse 400 MHz spectrometer
using deuterochloroform as an internal standard. Low-resolution
mass spectra were recorded on a VG TRIO-2 mass spectrometer
under electron impact conditions at an ionising potential of 70 eV
and/or with a Hewlett Packard GCeMS HP5890 (GC) with capillary
column and HP 5971 (MS). Accurate mass analyses were performed
and reported on a VG-ZAB-E under EI conditions by the EPSRC
National Mass Spectrometry Service Centre (Swansea) using the EI
Peak Match on Mþ method. Reactions were carried out under an
atmosphere of dry nitrogen unless otherwise stated.
121.6 (3JCeF¼19.2 Hz), 118.8, 71.2 (d, 4JCeF¼6.2 Hz), 25.9, 18.1; LRMS
(EI): m/z 227 [Mþ] 209, 140, 103, 86, 69; HRMS (ES): calcd for
C12H17FNO2 [MþNH4]þ 226.1238; found 226.1237.
4.2.3. 5,6-Difluoro-2-[(3-methylbut-2-en-1-yl)oxy]-benzaldehyde
5d. Following the general procedure the title compound was iso-
lated as a colourless oil (1.37 g, 95%): Rf 0.53 (1:3 diethyl ether);
vmax (NaCl)/cmꢁ1 (thin film) 2869, 1695, 1602, 1481, 1378, 1262,
1074; 1H NMR (400 MHz, CDCl3):
d
¼10.41 (1H, s, COeH), 7.31 (1H,
q, J¼9.0 Hz, AreH); 6.67e6.73 (1H, m, HeAr); 5.50e5.43 (1H, m,
HeC]C); 4.62 (2H, d, J¼6.5 Hz, CH2); 1.81 (3H, s, CH3); 1.75 (3H, s,
4
4.2. Preparation of 2-(3-methylbut-2-enyloxy)-benzaldehyde 5a
CH3); 13C NMR (100 MHz, CDCl3):
d
¼189.4, 157.1 (dd, JCeF¼3.67,
2
3
2.20 Hz), 149.9 (dd, JCeF¼266.30, JCeF¼13.21 Hz), 144.8, (dd,
3
3
To
a
flame-dried two-necked flask containing dry DMF
2JCeF¼242.82, JCeF¼12.47 Hz), 139.4, 122.32 (dd, JCeF¼19.07,
4JCeF¼2.93 Hz), 118.8, 115.5 (d, 4JCeF¼5.87 Hz), 108.0 (t,
4JCeF¼4.77 Hz), 66.5, 25.7, 18.3; LRMS (EI): m/z 226 [Mþ] HRMS (EI):
calcd for C12H16F2NO2 [MþNH4]þ 244.1144; found 244.1146.
(100 mL), were added salicylaldehyde (5.21 g, 42.7 mmol),
4-bromo-2-methylbut-2-ene (7.00 g, 47.0 mmol), finely ground
anhydrous potassium carbonate (23.6 g, 171 mmol) and potassium
iodide (0.714 g, 4.30 mmol). The solution was left to stir at an am-
bient temperature under an atmosphere of nitrogen for 2.5 h.
Analysis of the reaction mixture by TLC (1:3 diethyl ether/light
petroleum spirit) showed the presence of a new compound with an
Rf of 0.480. The reaction mixture was poured into water and par-
titioned between diethyl ether. The aqueous phase was isolated and
then extracted with diethyl ether (6ꢂ20 mL). The combined or-
ganic extracts were combined, dried over anhydrous magnesium
sulfate, filtered and concentrated in vacuo to afford a yellow oil.
Purification of the crude material was carried out by chromatog-
raphy on silica,15 eluted with diethyl ether/light petroleum spirit
(1:3). This provided the title compound, 5a, (7.02 g, 86%) as a col-
ourless oil: Rf 0.48 (1:3 diethyl ether/light petroleum spirit): vmax
(NaCl)/cmꢁ1 (thin film) 3034, 1686, 1598, 1286; 1H NMR (400 MHz,
4.2.4. 3,6-Difluoro-2-[(3-methylbut-2-en-1-yl)oxy]- benzaldehyde 5e.
Following the general procedure the title compound was isolated as
a colourless oil (1.29 g, 91%): Rf 0.64 (1:3 diethyl ether/light petroleum
spirit): vmax (NaCl)/cmꢁ1 (thin film) 3060, 1690, 1606, 1582, 1444,
1284; 1H NMR (400 MHz CDCl3):
d
¼10.35 (1H, s, COeH), 7.24e7.31
(1H, m, AreH); 6.81 (1H, td, J¼9.3, 3.4 Hz, HeAr); 5.45e5.53 (1H, m,
HeC]C); 4.76 (2H, d, J¼7.3 Hz, CH2); 1.77 (3H, s, CH3); 1.68 (3H, s,
CH3). 13C NMR (100 MHz, CDCl3):
d
¼186.7, 157.7 (dd, JCeF¼260.43,
2
2
4
4JCeF¼2.93 Hz), 151.6 (dd, JCeF¼245.02, JCeF¼3.67 Hz), 148.8, (dd,
3JCeF¼13.20, 4JCeF¼5.13 Hz), 141.1, 122.2 (dd, 3JCeF¼22.74,
3
4
3JCeF¼11 Hz), 119.5 (dd, JCeF¼9.54, JCeF¼1.47 Hz), 118.5, 110.8 (dd,
3JCeF¼23.47 and 4J¼7.34 Hz), 71.2 (d, JCeF¼6.60 Hz), 25.6, 17.8; LRMS
(EI): m/z 226 [Mþ] HRMS (EI): calcd for C12H16F2NO2 [MþNH4]þ
244.1144; found 244.1148.
CDCl3):
d
¼10.46 (1H, s, COeH), 7.78 (1H, dd J¼1.8, 7.9 Hz, AreH);
7.50e7.45 (1H, m, HeAr); 6.97e6.93 (2H, m, HeAr); 5.48e5.43 (1H,
m, HeC]C); 4.59 (2H, d, J¼6.8 Hz, CH2); 1.76 (3H, s, CH3); 1.71 (3H,
4.2.5. 4,5-Difluoro-2-[(3-methylbut-2-en-1-yl)oxy]-benzaldehyde
5f. Following the general procedure the title compound was iso-
lated as a colourless oil (1.34 g, 92%): Rf 0.66 (1:3 diethyl ether/light
petroleum spirit); vmax (NaCl)/cmꢁ1 (thin film) 3080, 1696, 1600,
s, CH3); 13C NMR (100 MHz, CDCl3):
d
¼189.6, 161.1, 138.4, 135.6,
127.9, 124.8, 120.3, 118.8, 112.7, 65.2, 25.5, 18.0; LRMS (EI): m/z 191,
122, 104.93, 69, 51. HRMS (ES): calcd for C12H15O2 [Mþ] 191.1067;
found 191.1066.
1588, 1480, 1284; 1H NMR (400 MHz CDCl3):
d¼10.38 (1H,
d J¼3.0 Hz, COeH), 7.68 (1H, dt, J¼3.0, 10 Hz, AreH); 6.84 (1H, dd,
J¼6.0, 10 Hz, AreH); 5.44e5.54 (1H, m, HeC]C); 4.63 (2H, d,
J¼6.8 Hz, CH2); 1.85 (3H, s, CH3); 1.79 (3H, s, CH3); 13C NMR
4.2.1. 5-Fluoro-2-[(3-methylbut-2-en-1-yl)oxy benzaldehyde 5b.
Following the general procedure16 the title compound was isolated
(8.71 g, 82%) as a crystalline solid: Rf 0.80 (1:3 diethyl ether/light
petroleum spirit), mp 45e46 ꢀC (from hexane); vmax (NaCl)/cmꢁ1
(thin film) 2866, 1686, 1612, 1490, 1428, 1384, 1266, 1200, 1148; 1H
3
4
(100 MHz, CDCl3):
d
¼186.7, 158.2 (dd, JCeF¼8.44, JCeF¼1.83 Hz),
2
3
2
154.7 (dd, JCeF¼258.96, JCeF¼14.67 Hz), 144.8 (dd, JCeF¼244.29,
3JCeF¼13.21 Hz), 139.6, 121.3 (t, JCeF¼3.30 Hz), 118.0, 115.9 (dd,
4
4
3
NMR (400 MHz, CDCl3):
d
¼10.41 (1H, d, J¼1.3 Hz, COeH), 7.48 (1H,
3JCeF¼18.3, JCeF¼2.93 Hz), 102.9 (d, JCeF¼21.27), 66.32, 25.56,
18.09; LRMS (EI): m/z 226 [Mþ] HRMS (EI): calcd for C12H16F2NO2
[MþNH4]þ 244.1144; found 244.1146.
dd, J¼3.3, 8.3 Hz, AreH); 7.22 (1H, ddd, J¼1.3, 3.3, 8.3 Hz, HeAr);
6.95 (1H, dd, J¼3.3, 8.3 Hz, HeAr); 5.49e5.44 (1H, m, HeC]C);
4.60 (2H, d, J¼6.6 Hz, CH2); 1.79 (3H, d, J¼1.1 Hz, CH3); 1.74 (3H, br s,
CH3); 13C NMR (100 MHz, CDCl3):
d
¼189.0 (d, 4JCeF¼1.54 Hz), 158.1
4.2.6. 4-Fluoro-2-[(3-methylbut-2-en-1-yl)oxy] benzaldehyde 5g.
Following the general procedure the title compound was isolated as
a yellow oil (0.34 g, 23%): Rf 0.78 (1:3 diethyl ether/light petroleum
spirit); vmax (NaCl)/cmꢁ1 (thin film) 2875, 1695, 1612, 1486, 1394,
4
2
(d, JCeF¼1.54 Hz), 155.7, (d, JCeF¼241.38 Hz), 139.2, 125.5 (d,
3JCeF¼5.38 Hz), 122.5 (d, JCeF¼23.06 Hz), 118.8, 114.8, (d,
3
3JCeF¼6.92 Hz),113.9 (d, 3JCeF¼23.06 Hz), 66.3, 25.9,18.4. LRMS (EI):
m/z 226 [MþþNH4], 209, 140, 103, 86, 69. HRMS (ES): calcd for
C12H17FNO2 [MþNH4]þ 226.1238; found 226.1237.
1258, 1228, 1069; 1H NMR (400 MHz, CDCl3):
d
¼10.38 (1H, d,
J¼0.8 Hz COeH), 7.86 (1H, dd J¼7.0, 8.5 Hz, AreH); 6.63e6.76 (2H,
m, HeAr); 5.44e5.54 (1H, m, HeC]C); 4.62 (2H, d, J¼6.8 Hz, CH2);
1.82 (3H, s, CH3); 1.78 (3H, s, CH3); 13C NMR (100 MHz, CDCl3):
4.2.2. 3-Fluoro-2-[(3-methylbut-2-en-1-yl)-oxybenzaldehyde
5c. Following the general procedure the title compound was iso-
lated (7.97 g, 75%) as a colourless oil: Rf 0.76 (1:3 diethyl ether/light
d
¼169.6, 167.1 (d, 2JCeF¼254.45 Hz), 163.7 (d, JCeF¼13.84 Hz), 140.3,
4
132.1 (d, JCeF¼11.53 Hz), 117.8, 109.4 (d, JCeF¼2.31 Hz), 107.1 (d,

10044
P. Brawn et al. / Tetrahedron 68 (2012) 10040e10048
3
3JCeF¼22.29 Hz), 104.3 (d, JCeF¼23.83 Hz), 62.3, 25.8, 18.1; LRMS
(EI): m/z 227 [Mþ] 209, 140, 103, 86, 69. HRMS (ES): calcd for
C12H17FNO2 [MþNH4]þ 226.1238; found 226.1239.
61.2, 30.7, 28.4, 25.8, 18.2; LRMS (EI): m/z 363 (MþNH4)þ; HRMS
(ES): calcd for C20H31N2O4 [MþNH4]þ 363.2278; found [363.2279].
4.3.1. 1-{5-Fluoro-2-[(3-methylbut-2-en-1-yl)oxy]phenyl}-3-N-Boc-
methylaminoprop-2-yn-o1 4b. Following the general procedure the
title compound was isolated as a yellow oil (0.80 g, 45%): Rf 0.55 (3:7
ethyl acetate/light petroleum spirit); vmax (NaCl)/cmꢁ1 (thin film)
3412, 2924, 2228, 1674, 1598, 1492, 1246, 1190; 1H NMR (400 MHz,
4.2.7. 3,5-Difluoro-2-[(3-methylbut-2-en-1-yl)oxy]-benzaldehyde
5h. Following the general procedure the title compound was iso-
lated as a colourless oil (1.03 g, 79%): Rf 0.64 (1:3 diethyl ether/light
petroleum spirit); vmax (NaCl)/cmꢁ1 (thin film) 3090, 1695, 1610,
1586, 1484, 1279; 1H NMR (400 MHz CDCl3):
d¼10.29 (1H, d,
CDCl3):
d
7.34e7.28 (m,1H, AreH), 6.96 (dd,1H, J¼8.0, 3.0 Hz, AreH),
J¼1.8 Hz, COeH), 7.29 (1H, ddd J¼1.8, 3.1 and 7.9 Hz, AreH); 7.09
(1H, ddd, J¼3.1, 7.9 and 10.9 Hz, HeAr); 5.49e5.43 (1H, m, HeC]
C); 4.68 (2H, d, J¼7.5 Hz, CH2); 1.74 (3H, s, CH3); 1.20 (3H, s, CH3);
6.84 (dd, 1H, J¼8.9, 4.4 Hz, AreH), 5.68 (d, 1H, J¼5.3 Hz, CHeOH),
5.47 (bd s, 1H, CH]C), 4.77e4.66 (m, 1H, NH), 4.57 (d, 2H, J¼4.0 Hz,
CH2O), 4.03 (d, 2H, J¼3.8 Hz, CH2eNH), 3.12 (d, 1H, J¼5.3 Hz, OH),
13C NMR (100 MHz, CDCl3):
d
¼188.1, shoulder, 157.6 (dd,
1.80 (s, 3H, CH3eC]C), 1.74 (s, 3H, CH3eC]C), 1.46 (s, 9H, (CH3)3C);
2JCeF¼247.52 and JCeF¼10.76 Hz), 155.8 (dd, JCeF¼252.90,
13C NMR (100 MHz, CDCl3):
d
¼156.9 (d, JCeF¼239.89 Hz), 153.1,
3
2
2
3
4
3JCeF¼9.99 Hz), 145.9 (dd, JCeF¼15.37 and JCeF¼3.80 Hz), 141.7,
152.1 (d, 4JCeF¼2.2 Hz), 138.7, 130.5 (d, 4JCeF¼6.6 Hz), 119.2, 115.3 (d,
3JCeF¼22.74 Hz), 114.9 (d, 3JCeF¼24.21 Hz), 113.2 (d, 4JCeF¼8.07 Hz),
82.8, 81.6, 80.1, 66.0, 61.0 (d, 4JCeF¼1.5 Hz), 30.75, 28.32, 25.75,18.25;
LRMS (EI): m/z 381 (MþNH4)þ; HRMS (ES): calcd for C20H30FN2O4
[MþNH4]þ 381.2184; found [381.2188].
3
3
131.2 (dd, JCeF¼7.69, 2.31 Hz), 118.3, 110.8 (dd, JCeF¼26.91 and
23.06 Hz), 108.8 (dd, JCeF¼23.06 and 3.84 Hz), 71.4 (d,
3JCeF¼5.4 Hz), 25.8, 17.9; LRMS (EI): m/z 244 [MþþNH4]þ, 226, 175,
137, 86, 69. HRMS (ES): calcd for C12H16F2NO2 [MþNH4]þ 244.1144;
found 244.1146.
4.3.2. 1-{3-Fluoro-2-[(3-methylbut-2-en-1-yl)oxy]phenyl}-3-N-Boc-
methylaminoprop-2-yn-o1 4c. Following the general procedure
the title compound was isolated as a yellow oil (2.0 g, 55%): Rf
0.50 (3:7 ethyl acetate/light petroleum spirit); vmax (NaCl)/cmꢁ1
(thin film) 3356, 2978, 2931, 2404, 1694, 1476; 1H NMR
4.2.8. 6-Fluoro-2-[(3-methylbut-2-en-1-yl)oxy]-benzaldehyde
5i. Following the general procedure the title compound was iso-
lated as a colourless oil (1.01 g, 95%): Rf 0.74 (1:3 diethyl ether/light
petroleum ether); vmax (NaCl)/cmꢁ1 (thin film) 2869, 1695, 1602,
1469, 1380, 1262, 1216, 1068; 1H NMR (400 MHz CDCl3):
d
¼10.45
(400 MHz, CDCl3):
d
7.30 (bd d, J¼7.3 Hz, 1H, AreH), 7.11e6.99
(1H, s, COeH), 7.45 (1H, td J¼6.3 and 7.9 Hz, AreH); 6.77 (1H, d,
J¼8.8 Hz, HeAr); 6.71 (1H, dd, J¼8.8 and 10.0 Hz, HeAr); 5.42e5.53
(1H, m, HeC]C); 4.64 (2H, d, J¼6.5 Hz, CH2); 1.81 (3H, s, CH3); 1.76
(m, 2H, AreH), 5.71e5.64 (m, 1H, CHeOH), 5.59e5.51 (m, 1H,
CH]C), 4.70e4.64 (m, 3H, NH and CH2O), 4.02 (d, 2H, J¼4.0 Hz,
CH2eNH), 3.00 (d, 1H, J¼6.2 Hz, OH), 1.79 (s, 3H, CH3eC]C), 1.79
(s, 3H, CH3eC]C), 1.45 (s, 9H, (CH3)3C); 13C NMR (100 MHz,
(3H, s, CH3). 13C NMR (100 MHz, CDCl3):
d
¼187.6 (d, 4JCeF¼1.47 Hz),
162.6 (d, JCeF¼246.49 Hz), 161.6 (d, 3J¼22.01 Hz), 139.1, 135.8 (d,
JCeF¼711.74 Hz), 118.6, 114.4 (d, J¼8.80 Hz), 108.5 (d, J¼8.80 Hz),
108.4 (d, J¼8.80 Hz), 66.2, 25.8, 18.3. LRMS (EI): m/z 227 [Mþ] 209,
140, 103, 86, 69. HRMS (ES): calcd for C12H17FNO2 [MþNH4]þ
226.1238; found 226.1234.
CDCl3):
155.3
(d,
2JCeF¼247.53 Hz), 144.5, 143.9
(d,
2
3JCeF¼12.30 Hz), 139.9, 135.2, 123.7 (d, JCeF¼7.69 Hz), 122.9 (d,
4
4JCeF¼3.07 Hz), 119.6, 117.0 (d, JCeF¼19.22 Hz), 82.6, 82.3, 79.9,
3
4
70.5 (d, JCeF¼6.15 Hz), 60.9, 30.7, 38.3, 25.8, 18.0; LRMS (EI): m/z
381 (MþNH4)þ; HRMS (ES): calcd for C20H30FN2O4 [MþNHþ4 ]
381.2184; found [381.2184].
4.3. Preparation of 1-{2-[(3-methylbut-2-en-1-yl)oxy] phe-
nyl}-3-N-Boc-methylaminoprop-2-yn-o1 4a
4.3.3. 1-{5,6-Difluoro-2-[(3-methylbut-2-en-1-yl)oxy] phenyl}-3-N-
Boc-methylaminoprop-2-yn-o1 4d. Following the general pro-
cedure the title compound was isolated as a yellow oil (0.62 g, 35%):
Rf 0.50 (3:7 ethyl acetate/light petroleum spirit); vmax (NaCl)/cmꢁ1
(thin film) 3422, 2914, 2228, 1672, 1598, 1476; 1H NMR (400 MHz,
N-Boc-propargylamine (0.30 g, 1.94 mmol) was dissolved in THF
(20 mL) at ꢁ78 ꢀC in a flame-dried round-bottom flask. To this so-
lution was added dropwise LDA (1.80 M in heptane 2.11 mL,
3.80 mmol) to effect alkynide formation. The solution was left to
stir at ꢁ78 ꢀC for 60 min whereupon 5a (0.43 g, 2.25 mmol) was
added in one portion. The reaction mixture was left to stir for
a further 30 min and then allowed to reach ambient temperature.
TLC analysis of the reaction mixture (3:7 ethyl acetate/light pe-
troleum spirit) showed the presence of a slower moving compound
Rf 0.41. The reaction mixture was quenched by the addition of
a saturated aqueous solution of ammonium chloride (20 mL). The
solvent was removed in vacuo and the mixture partitioned be-
tween water and dichloromethane. The organic phase was isolated
and washed with water (3ꢂ20 mL), dried over anhydrous magne-
sium sulfate, filtered and concentrated in vacuo to give the crude
product. Purification by column chromatography on silica (3:7 ethyl
acetate/light petroleum spirit) provided the title compound 4a as
a yellow oil (0.46 g, 56% yield): vmax (NaCl)/cmꢁ1 (thin film) 3455,
CDCl3):
d
7.06 (d, J¼9.5 Hz, 1H, AreH), 6.67e6.57 (m, 1H, AreH),
5.74 (d, J¼10.8 Hz, 1H, CHeOH), 5.52e5.42 (m, 1H, CH]C),
4.66e4.51 (m, 3H, NH and CH2O), 3.96 (d, 2H, J¼2.8 Hz, CH2eNH),
3.69 (d, 1H, J¼10.8 Hz, OH), 1.81 (s, 3H, CH3eC]C), 1.76 (s, 3H,
CH3eC]C), 1.44 (s, 9H, (CH3)3C); 13C NMR (100 MHz, CDCl3); 158.5
3
4
2
(dd, JCeF¼16.87, JCeF¼4.40 Hz), 153.6 (dd, JCeF¼272.16 Hz,
3JCeF¼13.20 Hz), 152.7, 144.9 (dd, 2JCeF¼241.35 Hz, 3JCeF¼12.47 Hz),
3
4
139.4, 122.2 (dd, JCeF¼17.61 Hz, JCeF¼1.47 Hz), 118.6, 116.0 (dd,
3JCeF¼18.34 Hz, JCeF¼2.20 Hz), 107.7 (dd, JCeF¼6.60, 3.30 Hz),
82.2, 81.4, 79.9, 66.4, 60.3, 30.7, 28.3, 25.8, 18.3; LRMS (EI): m/z 399
(MþNH4)þ; HRMS (ES): calcd for C20H29F2N2O4 [MþNH4]þ
399.2090; found [399.2095].
4
4
4.3.4. 1-{3,6-Difluoro-2-[(3-methylbut-2-en-1-yl)oxy] phenyl}-3-N-
Boc-methylaminoprop-2-yn-o1 4e. Following the general procedure
the title compound was isolated as a yellow oil (0.67 g, 37%): Rf 0.38
(3:7 ethyl acetate/light petroleum spirit); vmax (NaCl)/cmꢁ1 (thin
film) 3422, 2914, 2230,1677,1596, 1476; 1H NMR (400 MHz, CDCl3):
2980, 2932, 2252, 1709, 1601; 1H NMR (400 MHz, CDCl3):
d 7.51 (dd,
1H, J¼7.5, 1.7 Hz, AreH), 7.30 (dt, 1H, J¼8.2, 1.7 Hz, AreH), 7.0 (dt,
1H, J¼7.5, 0.9 Hz, AreH), 6.92 (d, 1H, J¼8.2 Hz, AreH), 5.69 (dt, 1H,
J¼6.0 and 1.8 Hz, CHeOH), 5.50e5.46 (m, 1H, CH]C), 4.68 (s, 1H,
NH), 4.60 (d, 2H, J¼6.5 Hz, CH2O), 4.02 (d, 2H, J¼4.3, CH2eNH), 3.16
(d,1H, J¼6.1 Hz, OH), 1.79 (br s, 3H, CH3eC]C), 1.74 (s, 3H, CH3eC]
d
7.02 (ddd, J¼10.9, 9.2, 5.0 Hz, 1H, AreH), 6.76 (ddd, J¼9.2, 9.0,
3.7 Hz, 1H, AreH) 5.71 (d, J¼10.5 Hz, 1H, CHeOH), 5.57 (d, J¼7.2 Hz,
1H, CH]C), 4.74e4.60 (m, 3H, NH and CH2O), 3.97 (bd s, 2H,
CH2eNH), 3.53 (d,1H, J¼10.5 Hz, OH),1.81 (s, 3H, CH3eC]C),1.75 (s,
3H, CH3eC]C), 1.44 (s, 9H, (CH3)3C); 13C NMR (100 MHz, CDCl3):
C), 1.44 (s, 9H, (CH3)3C); 13C NMR (100 MHz, CDCl3):
138.6, 129.6, 128.9, 122.9, 120.8, 119.4, 112.1, 82.4, 82.3, 80.0, 65.2,
d
¼156.2, 155.3,
2
4
155.7 (dd, JCeF¼273.63, JCeF¼2.93 Hz), 152.8, 152.1 (dd,

P. Brawn et al. / Tetrahedron 68 (2012) 10040e10048
10045
2JCeF¼254.56 Hz, 4JCeF¼2.20 Hz), 146.4 (dd, 3JCeF¼13.94 Hz,
round-bottom flask containing dichloromethane (20 mL) and
charged with a magnetic stirrer. To the stirred solution was added
octacarbonyl dicobalt (1.36 g, 4.0 mmol), which was then left to stir
for 10 min. TLC analysis of the reaction mixture showed the presence
of a faster moving compound Rf 0.6 (DCM). To the reaction mixture
was added hexane (30 mL) and silica (1 g). The solvent was then re-
moved, in vacuo, leaving the cobalt complex adsorbed onto the silica
medium. Extraction of the silica with dichloromethane (30 mL) and
solvent removal in vacuo, provided the title compound 6a as a red oil
(1.84 g, 79%), which required no further purification. vmax (NaCl)/
cmꢁ1 (thin film)2090, 2050, 2024,1600,1484,1454,1382,1286,1230;
4JCeF¼3.70 Hz), 140.4, 119.1, 118.4
(dd,
3JCeF¼16.14 Hz,
3
4
4JCeF¼2.20 Hz), 116.6 (dd, JCeF¼22.01 Hz, JCeF¼10.30 Hz), 110.4
3
4
(dd, JCeF¼24.21, JCeF¼8.10 Hz), 82.5, 81.1, 80.5, 71.0 (d,
4JCeF¼7.34 Hz), 66.4, 30.6, 28.3, 25.9, 18.1; LRMS (EI): m/z 399
(MþNH4)þ; HRMS (ES): calcd for C20H29F2N2O4 [MþNH4]þ
399.2090; found [399.2091].
4.3.5. 1-{4,5-Difluoro-2-[(3-methylbut-2-en-1-yl)oxy] phenyl}-3-N-
Boc-methylaminoprop-2-yn-o1 4f. Following the general procedure
the title compound was isolated as a yellow oil (0.60 g, 34%): Rf 0.38
(3:7 ethyl acetate/light petroleum spirit); vmax (NaCl)/cmꢁ1 (thin
film) 3425, 2924, 2228, 1675, 1602, 1477; 1H NMR (400 MHz,
1HNMR (400 MHz, CDCl3):
d
7.51 (d,1H, J¼7.4 Hz, AreH), 7.23(dd,1H,
J¼8.0, 7.4 Hz, AreH), 7.01 (d, 1H, J¼7.4 Hz, AreH), 6.89 (d, 1H,
J¼8.0 Hz, AreH), 6.21 (d, 1H, J¼4.5 Hz, CHeOH), 5.50 (bd s, 1H, CH]
C), 5.16 (bd s, 1H, NH), 4.66e4.27 (m, 4H, CH2O, CH2N), 4.24 (d, 1H,
J¼4.5, OH), 1.78 (br s, 3H, CH3eC]C), 1.75 (s, 3H, CH3eC]C), 1.46 (s,
CDCl3):
d
7.41 (dd, J¼10.5, 9.5 Hz,1H, AreH), 6.73 (dd, J¼11.8, 6.5 Hz,
1H, AreH), 5.67 (d, J¼5.3 Hz, 1H, CHeOH), 5.49e5.40 (m, 1H, CH]
C), 4.81e4.62 (m, 1H, NH), 4.54 (d, J¼4.3 Hz, 2H, CH2eO), 4.02 (d,
J¼4.3 Hz, 2H, CH2eNH), 3.53 (d, 1H, J¼5.3 Hz, OH), 1.81 (s, 3H,
CH3eC]C), 1.75 (s, 3H, CH3eC]C), 1.46 (s, 9H, (CH3)3C); 13C NMR
9H, (CH3)3C); 13C NMR (100 MHz, CDCl3):
d
¼156.2,154.8,138.3,131.6,
128.7, 127.8, 120.4, 127, 120.9. 119.3, 111.4, 102.0, 95.1, 80.2, 69.1, 64.8,
28.3, 25.7, 18.1; LRMS (EI): m/z 632 (MꢁHþ) HRMS (ES): calcd for
C26H26Co2NO10 [MꢁHþ] 632.0183; found [632.0196].
(100 MHz, CDCl3):
(dd,
d
¼158.5 (dd, 4JCeF¼16.9 Hz, 5JCeF¼4.4 Hz), 153.6
2JCeF¼272.2 Hz,
3JCeF¼13.2 Hz),
152.7,
144.9
(dd,
2JCeF¼241.4 Hz, JCeF¼12.5 Hz), 139.4, 122.2 (dd, JCeF¼17.6 Hz,
3
3
4JCeF¼1.5 Hz), 118.6, 116.0 (dd, JCeF¼18.3 Hz, JCeF¼2.0 Hz), 107.7
4.4.1. Hexacarbonyl[1-{5-fluoro-2-[(3-methylbut-2-en-1yl) oxy]phe-
nyl}-3-N-Boc-methylaminoprop-2-yn-o1]dicobalt 6b. Following the
general procedure the title compound was isolated as a red oil
(0.69 g, 71%): Rf 0.36 (DCM); vmax (NaCl)/cmꢁ1 (thin film) 2098,
2050, 2028, 1610, 1458: 1H NMR (400 MHz, CDCl3): 6.96e6.89 (m,
1H, AreH), 6.81 (bd s, 2H, AreH), 6.21 (d, 1H, J¼4.5 Hz, CHeOH),
5.59e5.51 (m, 1H, CH]C), 5.25e5.19 (m, 1H, NH), 4.56 (bd s, 2H,
CH2O), 4.36 (br s, 1H, CH2N), 3.75 (bd s, 1H, OH), 1.96e1.64 (m, 6H,
CH3eC]C), 1.47 (s, 9H, (CH3)3C); 13C NMR (100 MHz, CDCl3): 134.6,
119.1, 114.3, 112.3, 80.6, 68.5, 43.2, 28.3, 27.8, 22.2, 18.1; LRMS (EI):
m/z 672 [MꢁNaþ] HRMS (ES): calcd for C26H25Co2FNNaO10
[MþNaþ] 672.0097; found [672.0087].
3
4
4
5
(d, JCeF¼6.6 Hz, JCeF¼3.3 Hz), 82.2, 81.4, 79.9, 66.4, 60.3, 30.7,
28.3, 25.8, 18.3; LRMS (EI): m/z 399 (MþNH4)þ; HRMS (ES): calcd
for C20H29F2N2O4 [MþNH4]þ 399.2090; found [399.2091].
4.3.6. 1-{4-Fluoro-2-[(3-methylbut-2-en-1-yl)oxy]phenyl}-3-N-Boc-
methylaminoprop-2-yn-o1 4g. Following the general procedure the
title compound was isolated as a yellow oil (0.48 g, 28%): Rf 0.39 (3:7
ethyl acetate/light petroleum spirit); vmax (NaCl)/cmꢁ1 (thin film)
3346, 2968, 2398, 1690, 1602, 1476; 1H NMR (400 MHz, CDCl3):
d
7.24e7.08 (m, 1H, AreH), 6.69e6.60 (m, 2H, AreH), 5.67 (br s, 1H,
CHeOH), 5.50e5.42 (m, 1H, CH]C), 4.84e4.67 (m, 1H, NH), 4.57 (d,
2H, J¼5.8 Hz, CH2O), 4.02 (br s, 2H, CH2eNH), 3.38 (br s,1H, OH),1.81
(s, 3H, CH3eC]C), 1.76 (s, 3H, CH3eC]C), 1.46 (s, 9H, (CH3)3C); 13
C
4.4.2. Hexacarbonyl[1-{3-fluoro-2-[(3-methylbut-2-en-1yl)
oxy]
3
NMR (100 MHz, CDCl3):
d
¼164.4 (d, JCeF¼16.91 Hz), 147.9 (d,
phenyl}-3-N-Boc-methylaminoprop-2-yn-o1]dicobalt 6c. Following
the general procedure the title compound was isolated as a red oil
(2.66 g, 84%): Rf 0.28 (DCM) vmax (NaCl)/cmꢁ1 (thin film) 3080,
2914, 2228,1672,1598,1476; 1H NMR (400 MHz, CDCl3): 7.35 (d,1H,
J¼7.5 Hz, AreH), 7.11e6.97 (m, 2H, AreH), 6.18 (d, 1H, J¼3.8 Hz,
CHeOH), 5.50 (t, 1H, J¼6.9 Hz, CH]C), 5.40 (t, 1H, J¼6.0 Hz NH),
4.85e4.77 (m, 1H, CH2N), 4.58e4.44 (m, 2H, CH2), 4.27 (dd, 1H,
J¼15.7, 6.0 Hz, CH2N), 4.23 (d, 1H, J¼3.8 Hz, OH), 1.75 (s, 3H,
CH3eC]C), 1.69 (s, 3H, CH3eC]C), 1.47 (s, 9H, (CH3)3C): 13C NMR
(100 MHz, CDCl3): 138.6, 121.8, 119.6, 80.4, 77.3, 70.2, 68.4, 43.2,
28.3, 25.7, 22.2, 17.9; LRMS (EI): m/z 672 [MþNaþ] HRMS (ES): calcd
for C26H25Co2FNNaO10 [MþNaþ] 672.0097; found [672.0090].
4JCeF¼5.38 Hz), 137.6, 129.6 (d, 3JCeF¼9.9 Hz), 119.0 (d,
3JCeF¼23.06 Hz), 118.7, 106.7 (d, JCeF¼22.74 Hz), 114.9 (d,
3
3JCeF¼24.21 Hz),113.2 (d, 3JCeF¼13.84 Hz),100.3 (d, 3JCeF¼26.14 Hz),
89.6, 80.9, 77.2, 65.2 (d, 4JCeF¼2.31 Hz), 31.4, 28.3, 25.8, 18.3; LRMS
(EI): m/z 381 (MþNH4)þ; HRMS (ES): calcd for C20H30FN2O4
[MþNH4]þ 381.2184; found [381.2187].
4.3.7. 1-{3,5-Difluoro-2-[(3-methylbut-2-en-1-yl)oxy] phenyl}-3-N-
Boc-methylaminoprop-2-yn-o1 4h. Following the general pro-
cedure the title compound was isolated as a yellow oil (0.93 g, 54%):
Rf 0.40 (3:7 ethyl acetate/light petroleum spirit); vmax (NaCl)/cmꢁ1
(thin film) 3425, 2924, 2228, 1675, 1602, 1477; 1H NMR (400 MHz,
CDCl3):
d
7.09 (d, J¼8.4 Hz, 1H, AreH), 6.89e6.84 (m, 1H, AreH),
4.4.3. Hexacarbonyl[1-{5,6-difluoro-2-[(3-methylbut-2-en-1-yl)oxy]
phenyl}-3-N-Boc-methylaminoprop-2-yn-o1]dicobalt 6d. Following
the general procedure the title compound was isolated as a red oil
(0.31 g, 76%): Rf 0.25 (DCM); vmax (NaCl)/cmꢁ1 (thin film) 2914,
2052, 2028, 1609, 1598, 1476; 1H NMR (400 MHz, CDCl3): 7.06 (d,
1H, J¼9.4 Hz, AreH), 6.56 (d, 1H, J¼9.4 Hz, AreH), 6.26 (d, 1H,
J¼10.0 Hz, CHeOH), 5.50 (br s, 1H, CH]C), 5.13 (m, 1H, NH), 4.78 (d,
1H, J¼10 Hz, OH), 4.66e4.51 (d, 2H, J¼7.9 Hz, CH2), 4.41 (dd, 2H,
J¼6.5, 10.5 Hz, CH2N), 1.79 (s, 3H, CH3eC]C), 1.76 (s, 3H, CH3eC]
C), 1.45 (s, 9H, (CH3)3C): 13C NMR (100 MHz, CDCl3); 139.8, 117.4,
115.7, 107.23, 79.84, 68.7, 65.8, 42.7, 28.3, 25.7, 22.2, 18.1: LRMS (EI):
m/z 690 [MþNaþ] HRMS (ES): calcd for C26H25Co2F2NNaO10
[MþNaþ] 690.0003; found [690.0000].
5.68 (br s, 1H, CHeOH), 5.56e5.48 (m, 1H, CH]C), 4.73 (bd s, 1H,
NH), 4.63 (d, J¼7.0 Hz, 2H, CH2eO), 4.01 (bd s, 2H, CH2eN), 2.99 (d,
1H, J¼5.5 Hz, OH), 1.79 (s, 3H, CH3eC]C), 1.71 (s, 3H, CH3eC]C),
1.45 (s, 9H, (CH3)3C); 13C NMR (100 MHz, CDCl3):
d
¼156.5 (d,
2JCeF¼259.82 Hz), 155.6 (d, JCeF¼262.9 Hz), 152.1 (dd, JCeF¼11.5,
2
3
4JCeF¼2.3 Hz), 149.4, 140.3, 137.0 (d, JCeF¼21.5, JCeF¼2.31 Hz),
3
4
119.3, 109.7 (dd, 3JCeF¼24.6, 4JCeF¼2.31 Hz), 105.0 (dd, 3JCeF¼26.14,
4
23.06 Hz), 83.1, 81.7, 80.1, 70.7 (d, JCeF¼5.4 Hz), 60.2, 30.6, 28.3,
25.8, 18.0; LRMS (EI): m/z 399 (MþNH4)þ; HRMS (ES): calcd for
C20H29F2N2O4 [MþNH4]þ 399.2090; found [399.2091].
4.4. Preparation of hexacarbonyl[1-{2-[(3-methylbut-2-en-1-
yl)oxy]phenyl}-3-N-Boc-methylaminoprop-2-yn-o1] dicobalt
6a14
4.4.4. Hexacarbonyl[1-{3,6-difluoro-2-[(3-methylbut-2-en-1-yl)oxy]
phenyl}-3-N-Boc-methylaminoprop-2-yn-o1]dicobalt 6e. Following
the general procedure the title compound was isolated as a red oil
(0.66 g, 55%): Rf 0.22; vmax (NaCl)/cmꢁ1 (thin film) 2099, 2055,
1-{2-[(3-Methylbut-2-en-1-yl)oxy]phenyl}-3-N-Boc-methyl am-
inoprop-2-yn-o14a(1.27 g, 3.7 mmol)wasdissolvedina flame-dried

10046
P. Brawn et al. / Tetrahedron 68 (2012) 10040e10048
2028, 1612, 1598, 1476; 1H NMR (400 MHz, CDCl3): 7.01 (br s, 1H,
AreH), 6.77 (br s, 1H, AreH), 6.18 (br s, 1H, CHeOH), 5.54 (br s, 1H,
CH]C), 5.17 (br s, 1H, NH), 4.90e4.69 (m, 2H, CH2), 4.35 (bd s, 3H,
CH2N and OH), 1.87e1.63 (m, 6H, CH3eC]C), 1.44 (s, 9H, (CH3)3C);
13C NMR (100 MHz, CDCl3):118.5, 116.3, 110.3, 79.8, 70.8 (d,
4JCeF¼8.1 Hz), 69.0, 42.8, 28.3; 25.6, 22.0, 18.0; LRMS (EI): m/z 666
[MꢁHþ] HRMS (ES): calcd for C26H25Co2F2NO10 [MꢁHþ] 666.0038;
found [666.0026].
with dichloromethane (3ꢂ15 mL) and the combined organic layers
were dried over anhydrous magnesium sulfate, filtered and the sol-
vent removed in vacuo to afford the title compound as a red oil
(0.55 g, 94%): vmax (NaCl)/cmꢁ1 (thin film) 3583, 2980, 2857, 2091,
2053, 2021,1712,1506; 1H NMR (400 MHz, CDCl3): 7.26e7.22 (m,1H,
AreH), 7.15 (t, 1H, J¼7.2 Hz, AreH), 6.94 (t, 1H, J¼7.2 Hz, AreH), 6.83
(d, 1H, J¼8.0 Hz, AreH), 4.98e4.86 (m, 1H, NH), 4.62 (dd, 1H, J¼16.1
and 6.5 Hz, CH2), 4.47 (dd,1H, J¼16.1 and 6.5 Hz, CH2), 4.39 (ddd,1H,
J¼7.8, 3.0 and 1.3 Hz, CH2), 4.33 (d, 1H, J¼12.5 Hz, CH2), 4.25 (s, 1H,
AreCH), 2.46e2.35 (m, 1H, CHeCF) 1.45 (s, 9H, (CH3)3C), 1.44 (d, 3H,
J¼21.8 Hz, CH3), 1.32 (d, 3H, J¼22.3 Hz, CH3); 13C NMR (100 MHz,
4.4.5. Hexacarbonyl[1-{4,5-difluoro-2-[(3-methylbut-2-en-1-yl)oxy]
phenyl}-3-N-Boc-methylaminoprop-2-yn-o1]dicobalt 6f. Following
the general procedure the title compound was isolated as a red oil
(0.67 g, 67%): Rf 0.20 (DCM); vmax (NaCl)/cmꢁ1 (thin film) 2950,
2917, 2228, 2098, 2050, 1604, 1598, 1476; 1H NMR (400 MHz,
CDCl3): 7.43 (t, 1H, J¼10.0 Hz, AreH), 6.72 (dd, 1H, J¼6.3 and
11.8 Hz, AreH), 6.21 (br s, 1H, CHeOH), 5.50e5.42 (m, 1H, CH]C),
5.31 (br s, 1H, NH), 4.84 (br s, 1H, OH), 4.63e4.51 (m, 2H, CH2), 4.45
(d, 1H, J¼6.0 Hz, CH2N), 4.31 (dd, 1H, J¼6.0 and 15.4 Hz, CH2N), 1.79
(br s, 3H, CH3eC]C), 1.75 (s, 3H, CH3eC]C), 1.49 (s, 9H, (CH3)3C):
13C NMR (100 MHz, CDCl3): 138.8, 118.6, 115.8, 101.4, 81.0, 66.9,
65.6, 43.4, 28.3, 25.7, 18.1: LRMS (EI): m/z 690 [MþNa]þ HRMS (ES):
calcd for C26H25Co2F2NNaO10 [MþþNa]þ 690.0003; found
[689.9985].
CDCl3):
d¼155.5, 154.0, 130, 128.6, 124.7, 121.4, 117.3, 104.4, 97.7, 96.6
2
4
(d, JCeF¼165.3 Hz), 79.9, 68.1, 63.1 (d, JCeF¼9.2 Hz), 49.7 (d,
3JCeF¼24.2 Hz), 37.2 (d, JCeF¼5.4 Hz), 28.3, 25.9 (d, JCeF¼23.8 Hz),
4
3
24.5 (d, 3JCeF¼24.6 Hz): LRMS (EI): m/z 666.
4.5.1. Hexacarbonyl{3-(1-fluoro-1-methylethyl)-6-fluoro-4-(N-Boc-
methylaminoethynyl)chromane}dicobalt 7b. Following the general
procedure the title compound was isolated as a red oil (0.41 g, 62%):
Rf 0.65 (DCM); vmax (NaCl)/cmꢁ1 (thin film) 3586, 2995, 2098, 2055,
1692, 1500; 1H NMR (400 MHz, CDCl3): 7.01 (dd, 1H, J¼7.8, 3.0 Hz,
AreH), 6.87 (ddd, 1H, J¼9.0, 7.8, 3.0 Hz, AreH), 6.80 (dd, 1H, J¼9.0,
4.5 Hz, AreH), 5.04e4.88 (m, 1H, NH), 4.64 (dd, 1H, J¼16.1, 6.5 Hz,
CH2), 4.46 (dd, 1H, J¼16.1, 6.5 Hz, CH2), 4.40e4.31 (m, 1H, CH2),
4.31e4.25 (m, 1H, CH2), 4.23 (s, 1H, AreCH), 2.45e2.34 (m, 1H,
CHeCF), 1.45 (s, 9H, (CH3)3C), 1.44 (d, 3H, J¼22.1 Hz, CH3), 1.32 (d,
4.4.6. Hexacarbonyl[1-{4-fluoro-2-[(3-methylbut-2-en-1-yl)oxy]
phenyl}-3-N-Boc-methylaminoprop-2-yn-o1]dicobalt 6g. Following
the general procedure the title compound was isolated as a red oil
(0.92 g, 53%): Rf 0.25 (DCM); vmax (NaCl)/cmꢁ1 (thin film) 2230,
2226, 2051, 1610, 1597, 1476; 1H NMR (400 MHz, CDCl3): 7.51 (t, 1H,
J¼7.5 Hz AreH), 6.74e6.69 (m,1H, AreH), 6.64e6.58 (m,1H, AreH),
6.19 (d, 1H, J¼4.1 Hz, CHeOH), 5.52e5.42 (m, 1H, CH]C), 5.23e5.15
(m, 1H, NH), 4.59 (bd s, 1H, CH2N), 4.54e4.45 (m, 2H, CH2), 4.38 (d,
1H, J¼4.1 Hz, OH), 4.30 (dd, 1H, J¼15.8 and 6.0 Hz, CH2N), 1.78 (s,
3H, CH3eC]C), 1.75 (s, 3H, CH3eC]C), 1.47 (s, 9H, (CH3)3C): 13C
NMR (100 MHz, CDCl3): 156.3, 138.7, 127.9, 118.8, 106.9, 99.5, 95.2,
80.4, 67.9, 65.2, 43.2, 28.3, 25.6, 18.1: LRMS (EI): m/z 648 [MꢁH]þ
HRMS (ES): calcd for C26H25Co2FNO10 [MꢁH]þ 648.0132; found
[648.0127].
3H, J¼22.1 Hz, CH3): 13C NMR (100 MHz, CDCl3):
¼126.1, 118.3,
d
115.4, 103.4, 97.8, 95, 80.2, 68.5, 62.8, 49.9, 37.3, 28.3, 25.6, 24.4;
LRMS (EI): m/z 674 [MþNa]þ HRMS (ES): calcd for C26H25Co2F2N-
NaO9 [MþNa]þ 674.0054; found [674.0047].
4.5.2. Hexacarbonyl{3-(1-fluoro-1-methylethyl)-8-fluoro-4-(N-Boc-
methylaminoethynyl)chromane}dicobalt 7c. Following the general
procedure the title compound was isolated as a red oil (1.53 g, 58%):
Rf 0.60 (DCM); vmax (NaCl)/cmꢁ1 (thin film) 3582, 2986, 2080, 2054,
1682, 1509; 1H NMR (400 MHz, CDCl3): 7.08 (d,1H, J¼7.6 Hz, AreH),
6.97 (dd, J¼8.1, 1.5 Hz, 1H, AreH), 6.90, (dd, 1H, J¼7.6, 5.0 Hz, AreH),
4.96 (t, 1H, J¼6.6 Hz, NH), 4.64 (dd, 1H, J¼16.3, 6.6 Hz, CH2),
4.51e4.39 (m, 3H, CH, CH2), 4.30 (s, 1H, CH), 2.42 (dt, 1H, J¼11.4,
3.2 Hz, CH2), 1.51e1.43 (m, 12H, CH3, (CH3)3C), 1.32 (d, 3H,
4.4.7. Hexacarbonyl[1-{3,5-difluoro-2-[(3-methylbut-2-en-1-yl)oxy]
phenyl}-3-N-Boc-methylaminoprop-2-yn-o1]dicobalt 6h. Following
the general procedure the title compound was isolated as a red oil
(1.07 g, 67%): Rf 0.22 (DCM); vmax (NaCl)/cmꢁ1 (thin film) 3422, 2914,
2229, 2050, 2048, 1672, 1598, 1476; 1H NMR (400 MHz, CDCl3): 7.12
(d, 1H, J¼8.2 Hz, AreH), 6.84e6.73 (m, 1H, AreH), 6.15 (d, 1H,
J¼2.0 Hz, CHeOH), 5.51e5.37 (m,1H, CH]C and NH), 4.79e4.68 (m,
1H, CH2), 4.61 (d, 1H, J¼2.0 Hz, OH), 4.57e4.42 (m, 2H, CH2N), 4.29
(dd, 1H, J¼15.7, 5.7 Hz, CH2), 1.74 (bd s, 3H, CH3eC]C), 1.67 (s, 3H,
CH3eC]C), 1.47 (s, 9H, (CH3)3C): 13C NMR (100 MHz, CDCl3): 138.9,
119.5, 115.7, 80.4, 70.4 (d, 4JCeF¼6.9 Hz), 67.9 (d, 4JCeF¼3.1 Hz), 43.3,
28.3, 25.7, 17.9; LRMS (EI): m/z 666 [MꢁH]þ HRMS (ES): calcd for
C26H25Co2F2NO10 [MꢁH]þ 666.0038; found [666.0033].
J¼22.3 Hz, CH3); 13C NMR (100 MHz, CDCl3):
¼120.8, 120.7, 115.0,
d
101.7, 68.9, 63.4, 43.7, 28.3, 25.3, 24.6: LRMS (EI): m/z 650 [MꢁHþ]
HRMS (ES): calcd for C26H25Co2F2NO9 [MꢁHþ] 650.0089; found
[650.0081].
4.5.3. Hexacarbonyl{3-(1-fluoro-1-methylethyl)-5,6-difluoro-4-(N-
Boc-methylaminoethynyl)chromane}dicobalt 7d. Following the
general procedure the title compound was isolated as a red oil
(0.25 g, 95%): Rf 0.61 (DCM); vmax (NaCl)/cmꢁ1 (thin film) 3425,
2946, 2220, 2080, 2055, 1672, 1598; 1H NMR (400 MHz, CDCl3):
7.04e6.95 (m, 1H, AreH), 6.68e6.64, (m, 1H, AreH), 5.01e4.97 (m,
1H, NH), 4.53e4.46 (m, 3H, CH2 and CH2), 4.43 (ddd, J¼12.3, 4.8,
2.5 Hz, 1H, CH2), 4.33e4.29 (m, 1H, CH), 1.85e1.76 (m, 1H, CH),
1.48e1.38 (m, 12H, CH3 and (CH3)3C), 1.32 (d, 3H, J¼22.1 Hz, CH3);
13C NMR (100 MHz, CDCl3): 80.1, 62.9, 49.1, 28.3, 25.7, 24.4; LRMS
(EI): m/z 668 [MꢁH]þ HRMS (ES): calcd for C26H24Co2F3NO9
[MꢁH]þ 667.9994; found [667.9989].
4.5. Preparation of hexacarbonyl {3-(1-fluoro-1-methylethyl)-
4-(N-Boc-methylaminoethynyl)chromane} dicobalt 7a14
To a solution of hexacarbonyl[1-{2-[(3-methylbut-2-en-1-yl)oxy]
phenyl}-3-N-Boc-methylaminoprop-2-yn-o1]dicobalt 6a (1.10 g,
1.7 mmol) dissolved in dry dichloromethane (10 mL) and maintained
at a temperature of 0 ꢀC was added boron trifluouride diethyl
4.5.4. Hexacarbonyl{3-(1-fluoro-1-methylethyl)-5,8-difluoro-4-(N-
Boc-methylaminoethynyl)chromane}dicobalt
7e. Following the
etherate (0.25 g, 220
m
L, 1.8 mmol). The reaction mixture was left to
general procedure the title compound was isolated as a red oil
(0.46 g, 76%): Rf 0.58 (DCM) vmax (NaCl)/cmꢁ1 (thin film) 2914,
2228, 2055, 2040, 1598; 1H NMR (400 MHz, CDCl3); 7.04e6.92 (m,
1H, AreH), 6.49, (br s, 1H, AreH), 4.97 (br s, 1H, NH), 4.56e4.44 (m,
1H, CH2), 4.41e4.27 (m, 2H, CH and CH2), 3.95e3.78 (m, 2H, CH2),
stir for about 5 min underan atmosphere of nitrogen. Analysis by TLC
showed the presence of a new compound with an Rf of 0.49 (DCM).
The reaction mixture was quenched by the addition of a saturated
aqueous solution of sodium hydrogen carbonate (10 mL) and then
partitioned with dichloromethane. The aqueous phase was extracted
1.80e1.72 (m, 1H, CH), 1.49e1.35 (m, 15H, 2ꢂCH3 and (CH3)3C); 13
C

P. Brawn et al. / Tetrahedron 68 (2012) 10040e10048
10047
NMR (100 MHz, CDCl3):
d
¼116.0, 105.7,77.8, 67.1, 63.2, 48.2, 43.1,
(CH3)3C), 1.39 (d, 3H, J¼22.6 Hz, CH3); 13C NMR (100 MHz, CDCl3):
28.3, 25.7, 24.6; LRMS (EI): m/z 669 [MꢁH]þ HRMS (ES): calcd for
C26H24Co2F3NO9 [MꢁH]þ 667.9994; found [667.9977].
d
¼155.2,153.8,130,128.2,121.6,121.2,116.9, 96.3 (d, 2JCeF¼168.0 Hz),
92.8, 85.6, 78.3, 65.8, 64.2 (d, 4JCeF¼10.3 Hz), 47.4 (d, 3JCeF¼22.7 Hz),
4
3
28.3, 28.0 (d, JCeF¼5.1 Hz), 25.8 (d, JCeF¼24.9 Hz), 25.3 (d,
3JCeF¼24.2 Hz): LRMS (EI): m/z 365 [MþNH4]þ HRMS (ES): calcd for
C20H30FN2O3 [MþNH4]þ 365.2235; found [365.2237].
4.5.5. Hexacarbonyl{3-(1-fluoro-1-methylethyl)-6,7-difluoro-4-(N-
Boc-methylaminoethynyl)chromane}dicobalt 7f. Following the gen-
eral procedure the title compound was isolated as a red oil (0.21 g,
39%): Rf 0.56 (DCM); vmax (NaCl)/cmꢁ1 (thin film) 3425, 2915, 2050,
2025, 1672, 1598; 1H NMR (400 MHz, CDCl3): 7.16 (t, 1H, J¼9.4 Hz,
AreH), 6.67, (dd, 1H, J¼11.2, 6.9 Hz, AreH), 5.07e4.86 (m, 1H, NH),
4.65 (dd, 1H, J¼16.3 and 6.5 Hz, CH2), 4.44 (dd, 1H, J¼16.3 and
6.5 Hz, CH2), 4.33 (d, 2H, J¼3.3 Hz, CH2), 4.20 (s, 1H, AreCH),
2.40e2.30 (m, 1H, CFeCH) 1.51e1.39 (m, 12H, CH3 and (CH3)3C) 1.31
(d, 3H, J¼22.6 Hz, CH3); 63.1, 43.6, 28.3, 25.9, 24.4; LRMS (EI): m/z
687 [MþNH4]þ HRMS (ES): calcd for C26H28Co2F3N2O9 [MþNH4]þ
687.0405; found [687.0404].
4.6.1. 3-(1-Fluoro-1-methylethyl)-6-fluoro-4-(N-Boc-methyl-
aminoethynyl)chromane 8b. Following the general procedure the
title compound was isolated as a yellow oil (0.40 g, 97%): Rf 0.61
(ethyl acetate/hexane 3:7); vmax (NaCl)/cmꢁ1 (thin film) 3356,
2980, 2210, 1698, 1586, 1490, 1229; 1H NMR (400 MHz, CDCl3): 7.06
(dd, 1H, J¼9.0, 3.0 Hz, AreH), 6.85 (ddd, 1H, J¼9.0, 8.0, 3.0 Hz,
AreH), 6.75 (dd, 1H, J¼9.0, 4.0 Hz, AreH), 4.63 (br s, 1H, NH),
4.39e4.30 (m, 1H, CH2), 4.17e4.06 (m, 1H, CH2), 3.92 (d, 2H,
J¼4.0 Hz, CH2), 3.85 (br s, 1H, CH), 2.38e2.24 (m, IH, CH), 1.45 (s, 9H,
(CH3)3C), 1.46 (d, 3H, J¼22.3 Hz, CH3), 1.39 (d, 3H, J¼23.1 Hz, CH3):
2
4.5.6. Hexacarbonyl{3-(1-fluoro-1-methylethyl)-7-fluoro-4-(N-Boc-
methylaminoethynyl)chromane}dicobalt 7g. Following the general
procedure the title compound was isolated as a red oil (0.46 g, 76%):
Rf 0.58 (DCM); vmax (NaCl)/cmꢁ1 (thin film) 2935, 2210, 2045, 2025,
1645, 1598, 1476; 1H NMR (400 MHz, CDCl3): 7.51 (t, 1H, J¼7.8 Hz,
AreH), 6.76e6.65, (m, 1H, AreH), 6.64e6.52 (m, 1H, AreH),
5.29e5.17 (m, 1H, NH), 4.66e4.34 (m, 4H, CH2), 4.23 (br s, 1H, CH),
2.37 (d, 1H, J¼10.5 Hz, CH), 1.53e1.38 (m, 12H, CH3 and (CH3)3C)
13C NMR (100 MHz, CDCl3):
d
173.4, 157.1 (d, JCeF¼253.82 Hz),
3
4
123.7 (d, JCeF¼24.94 Hz), 122.8 (d, JCeF¼7.34 Hz), 119.5 (d,
4JCeF¼7.34 Hz), 117.8 (d, JCeF¼8.07 Hz), 115.76 (d, JCeF¼23.48 Hz),
4
3
2
96.2 (d, JCeF¼167.99 Hz), 93.7, 84.7, 78.8, 68.5, 64.4 (d,
4JCeF¼9.54 Hz), 47.12 (d, JCeF¼22.01 Hz), 28.3, 28.2, 25.7 (d,
3
3JCeF¼24.94 Hz), 25.3 (d, 3JCeF¼24.21 Hz); LRMS (EI): m/z 365 [M]þ
HRMS (ES): calcd for C20H25F2NO3 [M]þ 365.1797; found
[365.1800].
1.31 (d, 3H, J¼21.6 Hz); 13C NMR (100 MHz, CDCl3):
¼106.9, 104.5,
d
99.5, 80.5, 67.7, 62.9, 43.1, 36.4, 28.3, 25.8, 24.4; LRMS (EI): m/z 650
[MꢁHþ] HRMS (ES): calcd for C26H25Co2F2NO9 [MꢁHþ] 650.0089;
found [650.0079].
4.6.2. 3-(1-Fluoro-1-methylethyl)-8-fluoro-4-(N-Boc-methyl-
aminoethynyl)chromane 8c. Following the general procedure the
title compound was isolated as a yellow oil (0.22 g, 76%): Rf 0.54
(ethyl acetate/hexane 3:7); vmax (NaCl)/cmꢁ1 (thin film) 3480, 2914,
2228, 1680, 1599, 1476; 1H NMR (400 MHz, CDCl3): 7.10 (d, 1H,
J¼7.9 Hz, AreH), 6.96e6.90 (m, 1H, AreH), 6.83 (dd, 1H, J¼7.9,
5.1 Hz, AreH), 4.72 (br s, 1H, NH), 4.43 (dt, 1H, J¼11.8, 3.0 Hz, CH2),
4.22 (dd, 1H, J¼11.8, 5.1 Hz, CH2), 3.90 (d, 3H, J¼5.1 Hz, CH, CH2),
2.38e2.24 (m, IH, CH), 1.50 (d, 3H, J¼12.0 Hz, CH3), 1.43 (s, 9H,
(CH3)3C), 1.36 (d, 3H, J¼22.8 Hz, CH3): 13C NMR (100 MHz, CDCl3):
4.5.7. Hexacarbonyl{3-(1-fluoro-1-methylethyl)-6,8-difluoro-4-(N-
Boc-methylaminoethynyl)chromane}dicobalt 7h. Following the
general procedure the title compound was isolated as a red oil
(0.56 g, 71%): Rf 0.57 (DCM); vmax (NaCl)/cmꢁ1 (thin film) 3420,
2914, 2228, 2250, 2220, 1598; 1H NMR (400 MHz, CDCl3): 6.89, (d,
1H J¼8.3 Hz, AreH), 6.77 (ddd, 1H J¼10.7, 8.3, 2.9 Hz, Ar), 5.02 (t, 1H
J¼6.5 Hz, NH), 4.66 (dd, 1H J¼16.2, 6.5 Hz, CH2), 4.45 (dd, 1H,
J¼16.2, 6.5 Hz, CH2), 4.41e4.37 (m, 2H, CH2), 4.28 (br s,1H, CH), 2.42
(dt, 1H, J¼11.4, 3.5 Hz, CH), 1.45 (s, 9H, (CH3)3C), 1.47 (d, 3H
J¼21.9 Hz), 1.32 (d, 3H, J¼22.7 Hz, CH3); 13C NMR (100 MHz, CDCl3):
d
156.6 (d, 2JCeF¼248.69 Hz), 152.6 (d, 3JCeF¼19.07 Hz), 151.3, 142.2
(d, 3JCeF¼11.53 Hz), 124.8 (d, 4JCeF¼3.08 Hz), 120.4 (d,
4JCeF¼6.92 Hz), 114.4 (d, 3JCeF¼17.68 Hz), 96.1 (d, 2JCeF¼169.12 Hz),
93.7, 84.9, 78.8, 68.8, 64.4 (d,4JCeF¼9.99 Hz), 47.1 (d,
3
d
¼138.5,120.8,115.0, 77.2, 63.4, 43.7, 28.3, 26.1, 24.3; LRMS (EI): m/z
3JCeF¼22.29 Hz), 28.2, 28.29e28.13 (m), 25.5 (d, JCeF¼25.35 Hz),
687 [MþNH4]þ HRMS (ES): calcd for C26H28Co2F3N2O9 [MþNH4]þ
25.4 (d, 3JCeF¼24.60 Hz); LRMS (EI): m/z 365 [M]þ HRMS (ES): calcd
687.0405; found [687.0407].
for C20H25F2NO3 [M]þ 365.1797; found [365.1799].
4.6. Preparation of 3-(1-fluoro-1-methylethyl)-4-(N-Boc-
methylaminoethynyl)chromane 8a
4.6.3. 3-(1-Fluoro-1-methylethyl)-5,6-difluoro-4-(N-Boc-methyl-
aminoethynyl)chromane 8d. Following the general procedure the
title compound was isolated as a yellow oil (1.10 g, 96%): Rf 0.52
(ethyl acetate/hexane 3:7); vmax (NaCl)/cmꢁ1 (thin film) 3422,
2920, 2228, 1685, 1599, 1476; 1H NMR (400 MHz, CDCl3): 6.97 (dd,
1H, J¼9.4, 9.2 Hz, AreH), 6.55 (ddd, 1H, J¼9.2, 3.8 and 1.8 Hz),
4.65e4.54 (m, 1H, NH), 4.37e4.25 (m, 2H, CH2), 4.02 (br s, 1H, CH),
3.91 (m, 3H, CH, CH2), 1.44 (s, 9H, (CH3)3C), 1.42 (d, 3H, J¼21.6 Hz,
CH3), 1.28 (d, 3H, J¼23.8 Hz, CH3); 13C NMR (100 MHz, CDCl3):
To a solution of hexacarbonyl {3-(1-fluoro-1-methylethyl)-4-(N-
Boc-methylaminoethynyl)chromane} dicobalt 7a (1.28 g, 2.0 mmol)
in methanol (125 mL) was added cerium ammonium nitrate (CAN)
(6.03 g, 11.0 mmol). The solution was stirred at an ambient temper-
ature for about 30 min until the evolution of gas ceased. Analysis by
TLC showed thepresence of a newcompound with an Rf of0.50 (ethyl
acetate/hexane 3:7). The reaction mixture was quenched by the ad-
dition of a saturated aqueous solution of sodium hydrogen carbonate
(50 mL). The solvent, methanol, was removed in vacuo and the
resulting aqueous solution was extracted with diethyl ether
(4ꢂ25 mL). The combined organic extracts were dried over anhy-
drous magnesium sulfate and the solvent removed in vacuo to afford
the title compound as a light brown oil (0.55 g, 79%): vmax (NaCl)/
cmꢁ1 (thin film) 3356, 2982, 2204, 1694, 1586, 1490, 1229; 1H NMR
(400 MHz, CDCl3): 7.34 (dd, 1H, J¼7.5, 1.0 Hz, AreH), 7.14 (dd, 1H,
J¼7.5 and 1.4 Hz, AreH), 6.93 (dd, 1H, J¼7.5, 1.0 Hz, AreH), 6.80 (dd,
1H, J¼7.5, 1.4 Hz, AreH), 4.67e4.65 (m, 1H, NH), 4.39 (dt, 1H, J¼11.6,
2.9 Hz, CH2), 4.18e4.08 (m, 1H, CH2), 3.95e3.83 (m, 3H, CH, CH2),
2.41e2.30 (m, 1H, CHCF) 1.46 (d, J¼21.6 Hz, 3H, CH3), 1.45 (s, 9H,
4
2
d
155.2, 150.0 (dd, JCeF¼5.13, 2.20 Hz), 148.3 (dd, JCeF¼248.69,
2 3
3JCeF¼13.94 Hz), 144.8 (dd, JCeF¼240.62, JCeF¼12.47 Hz), 115.8
(dd, 3JCeF¼19.07, 4JCeF¼1.47 Hz), 112.0 (d, 3JCeF¼15.41 Hz), 111.7 (dd,
4JCeF¼5.87, 3.67 Hz), 95.9 (d, 2JCeF¼169.46 Hz), 83.6, 80.1, 78.0, 65.8,
4
3
63.4 (d, JCeF¼8.07 Hz), 46.5 (d, JCeF¼23.47 Hz), 30.7 (bd s) 28.3,
3
3
25.8 (d, JCeF¼23.48 Hz), 24.9 (d, JCeF¼24.94 Hz): LRMS (EI): m/z
401 [MþNH4]þ HRMS (ES): calcd for C20H24F3NO3 [MþNH4]þ
401.2047; found [401.2049].
4.6.4. 3-(1-Fluoro-1-methylethyl)-5,8-difluoro-4-(N-Boc-methyl-
aminoethynyl)chromane 8e. Following the general procedure the
title compound was isolated as a yellow oil (0.19 g, 73%): Rf 0.50
(ethyl acetate/hexane 3:7); vmax (NaCl)/cmꢁ1 (thin film) 2914, 2230,

10048
P. Brawn et al. / Tetrahedron 68 (2012) 10040e10048
1686, 1598; 1H NMR (400 MHz, CDCl3): 6.93 (ddd, 1H, J¼9.5, 9.0,
5.0 Hz, AreH), 6.58 (ddd, J¼9.5, 9.0, 3.5 Hz, 1H, AreH) 6.61 (br s, 1H,
NH), 4.49e4.39 (m, 2H, CH2), 4.02 (br s,1H, CH), 3.90 (br s, 2H, CH2),
2.34 (bd d, IH, J¼13.3 Hz, CH), 1.49e1.39 (m, 12H, CH3, (CH3)3C), 1.28
AreH), 6.64 (br s, 1H, NH), 4.41 (dt, J¼11.7, 2.6, Hz, 1H, CH2), 4.20
(dd, J¼11.7 and 5.3 Hz, 1H, CH2), 3.92 (d, J¼3.8 Hz, 2H, CH2), 3.87 (br
s, 1H, CH), 2.41e3.31 (m, IH, CH), 1.52e1.44 (m, 12H, CH3, (CH3)3C),
1.38 (d, 3H, J¼22.9 Hz, CH3); 13C NMR (100 MHz, CDCl3):
d 171.7,
(d, 3H, J¼22.3 Hz, CH3); 13C NMR (100 MHz, CDCl3):
d
155.4, 150.8,
162.0, 155.7 (d, 3JCeF¼12.47 Hz), 138.9 (dd, 3JCeF¼11.74,
3
4
131.0, 128.8, 114.3, 110.8, 106.2, 96.7, 92.5, 88.8, 80.2, 68.1, 63.7 (d,
3JCeF¼8.1 Hz), 46.6 (d, 3JCeF¼22.7, Hz), 28.9, 28.3, 25.9
(d,3JCeF¼24.2 Hz), 24.8 (d, 3JCeF¼24.9 Hz); LRMS (EI): m/z 383 [M]þ
HRMS (ES): calcd for C20H25F3NO3 [M]þ 383.1703; found
[383.1699].
4JCeF¼2.93 Hz), 110.9 (dd, JCeF¼23.47, JCeF¼2.93 Hz), 107.5
(dd,3JCeF¼23.47, JCeF¼3.67 Hz), 103.5 (dd, JCeF¼27.14, 21.27 Hz),
4
3
2
4
96.9, 94.5 (d, JCeF¼171.66 Hz), 90.3, 83.3, 68.4 (d, JCeF¼8.07 Hz),
4
3
64.9 (d, JCeF¼10.27 Hz), 47.3 (d, JCeF¼22.74 Hz), 28.7 (bd s), 27.9
(d, 3JCeF¼22.74 Hz), 25.8 (d, 3JCeF¼24.21 Hz), 25.3 (d,
3JCeF¼24.21 Hz); LRMS (EI): m/z 383 [M]þ HRMS (ES): calcd for
C20H24F3NO3 [M]þ 383.1703; found [383.1707].
4.6.5. 3-(1-Fluoro-1-methylethyl)-6,7-difluoro-4-(N-Boc-methyl-
aminoethynyl)chromane 8f. Following the general procedure the
title compound was isolated as a yellow oil (0.07 g, 91%): Rf 0.52
(ethyl acetate/hexane 3:7); vmax (NaCl)/cmꢁ1 (thin film) 3445, 3321,
2918, 2228, 1678, 1602, 1476; 1H NMR (400 MHz, CDCl3): 7.14 (dd,
1H, J¼10.2, 9.2 Hz, AreH), 6.62 (dd, 1H, J¼11.3, 7.0 Hz, AreH) 4.63
(br s, 1H, NH), 4.35 (dt, 1H, J¼11.5, 2.8 Hz, CH2), 4.10 (dd, 1H, J¼11.5,
5.6 Hz, CH2), 3.92 (d, 2H, J¼2.5 Hz, CH2), 3.80 (d, 1H, J¼2.5 Hz, CH),
2.37e2.25 (m, 1H, CH), 1.45 (s, 9H, (CH3)3C), 1.46 (d, 3H, J¼21.8 Hz,
CH3), 1.39 (d, 3H, J¼22.6 Hz, CH3): 13C NMR (100 MHz, CDCl3):
Acknowledgements
We would like to express our thanks to the SWAN alliance for
the studentship to P.B. and to Kingston University for their financial
support during this project. Special thanks to the EPSRC-MS service
at Swansea for their kind provision of accurate mass spectra and for
the excellent and efficient service they provide.
2
3
d
155.2, 148.3 (dd, JCeF¼248.69, JCeF¼14.67 Hz), 148.8 (dd,
2JCeF¼241.35,
3JCeF¼13.20 Hz),
144.8
(dd,
2JCeF¼240.62,
References and notes
3JCeF¼12.47 Hz), 115.8 (dd, JCeF¼19.07, JCeF¼1.47 Hz), 112.0 (d,
3JCeF¼16.14 Hz), 111.7 (dd, 4JCeF¼5.87, 4.47 Hz), 95.9 (d,
2JCeF¼167.99 Hz), 83.6, 80.1, 78.0, 65.8, 63.4 (d,4JCeF¼8.80 Hz), 46.5
3
4
1. Tyrrell, E.; Tesfa, K.-H.; Greenwood, I.; Mann, A. L. Bioorg. Med. Chem. Lett. 2008,
18, 1237e1240.
2. Nicholas, K. M. Acc. Chem. Res. 1987, 20, 207e214.
3
3
3. Tyrrell, E.; Tillett, C. Tetrahedron Lett. 1998, 39, 9535e9538.
(d, JCeF¼22.74 Hz), 32.8, 28.3, 25.8 (d, JCeF¼24.21 Hz), 24.9 (d,
3JCeF¼22.74 Hz); LRMS (EI): m/z 401 [MþNH4]þ HRMS (ES): calcd
for C20H24F3NO3 [MþNH4]þ 401.2047; found [401.2048].
4. Berge, J.; Claridge, S.; Mann, A. L.; Muller, C.; Tyrrell, E. Tetrahedron Lett. 1997,
38, 685e686; Tyrrell, E.; Millet, J.; Tesfa, K.-H.; Williams, N.; Mann, A. L.; Tillett,
C.; Tyrrell, E. Tetrahedron 2007, 63, 12769e12778.
5. Mann, A. L.; Muller, C.; Tyrrell, E. J. Chem. Soc., Perkin Trans. 1 1998, 1427e1438.
6. Brawn, P.; Greenwood, I.; Carew, M.; Tyrrell, E., unpublished results.
7. Teobold, B. J. Tetrahedron 2002, 58, 4133e4170 (review); Cobalt mediated cyc-
lisations: Fletcher, A. J.; Christie, S. D. R. J. Chem. Soc., Perkin Trans. 1 2000,
1657e1668.
8. Zificsak, C. A.; Mulder, J. A.; Hsung, R. P.; Rameshkumar, C.; Wei, L.-L. Tetrahe-
dron 2001, 57, 7575e7606; Blanchet, J.; Bonin, M.; Micouin, L. Org. Prep. Proceed.
Int. 2002, 34, 467e492.
9. Ji, Y.; Riera, A.; Verdaguer, X. Eur. J. Org. Chem. 2011, 1438e1442.
10. Copper-catalysed propargylic amination see: Detz, R. J.; Delville, M. M. E.;
Hiemstra, H.; van Maarseveen, J. H. Angew. Chem., Int. Ed. 2008, 47, 3777e3780;
Transition metal three-component coupling of enamines to a ‘Nicholas’ cation:
Roth, D.-K. Tetrahedron Lett. 1994, 21, 3505e3508; Nicholas reactions of amines:
Roth, K.-D.; Muller, U. Tetrahedron Lett. 1993, 34, 2919e2922.
11. Available from SigmaeAldrich no: 687146; CAS number 92136-395.
12. Alayrac, C.; Mioskowski, C.; Salaun, J.-P.; Durst, F. Synlett 1992, 73e76.
13. The use of Fe(NO3)3 see: Grove, D. D.; Miskevich, F.; Smith, C. C.; Corte, J. R.
Tetrahedron Lett. 1990, 31, 6277e6280; Muehldorf, A.; Guzman-Perez, A.; Kluge,
A. F. Tetrahedron Lett. 1994, 35, 8755e8758; The use of molecular iodine see:
Isobe, M.; Nishizawa, R.; Hosokawa, S.; Nishikawa, T. Chem. Commun. 1998,
2665e2676; The use of Ce(NO3)6(NH4)2 CAN see: Jacobi, P. A.; Zheng, W. Tet-
rahedron Lett. 1993, 16, 2585e2588; Betancourt, J. M.; Rodriguez, C. M.; Martin,
V. S. Tetrahedron Lett. 1998, 39, 9773e9776; Sagamanova, I. K.; Tumanov, V. V.;
Smit, W. A. Mendeleev Commun. 2008, 18, 205e206.
14. The NMR spectra may be incomplete for some dicobalt hexacarbonyl com-
plexes. This is due to signal broadening in the NMR sample of the complex that
is often associated with concentration effects. In addition some of the carbon
resonances are coincident and thus overlap in the corresponding 13C NMR
spectrum. We have provided accurate mass data for all metal complexes.
Where 13C NMR or partial 13C NMR data were obtained using a range of
techniques such as HSQC, HMBC and Dept Q.
4.6.6. 3-(1-Fluoro-1-methylethyl)-7-fluoro-4-(N-Boc-methyl-
aminoethynyl)chromane 8g. Following the general procedure the
title compound was isolated as a yellow oil (0.57 g, 98%): Rf 0.45
(ethyl acetate/hexane 3:7); vmax (NaCl)/cmꢁ1 (thin film) 3328, 2916,
2228, 1685, 1605, 1478; 1H NMR (400 MHz, CDCl3): 7.42 (d,
J¼7.4 Hz, 1H, AreH), 6.62e6.51 (m, 1H, AreH), 6.52 (dd, 1H J¼10,
2.3 Hz, AreH), 4.64 (br s, 1H, NH), 4.49 (d, 2H, J¼6.0 Hz, CH2), 4.30
(d, J¼11.5 Hz, 1H, CH2), 4.09e4.01 (m, 1H, CH2), 3.76 (br s, 1H, CH),
2.31e2.17 (m, IH, CH), 1.41e1.33 (m, 12H, (CH3)3C, CH3), 1.30 (d, 3H,
J¼22.8 Hz CH3); 13C NMR (100 MHz, CDCl3):
d 163.5 (d,
2
2JCeF¼245.76 Hz), 161.0 (d, JCeF¼248.69 Hz), 155.2, 130.95 (d,
3
4
4JCeF¼9.54 Hz), 128.9 (d, JCeF¼10.27 Hz), 124.8 (d, JCeF¼3.67 Hz),
3
3
108.6 (d, JCeF¼22.01 Hz), 106.9 (d, JCeF¼20.54 Hz), 96.2 (d,
2JCeF¼167.99 Hz), 85.2, 82.5, 78.6, 65.6, 63.3 (d, JCeF¼10.27 Hz),
3
3
4
47.1 (d, JCeF¼22.74 Hz), 28.3, 27.6 (d, JCeF¼5.14 Hz), 25.8 (d,
3JCeF¼24.94 Hz), 25.3 (d, 3JCeF¼24.94 Hz); LRMS (EI): m/z 365 [M]þ
HRMS (ES): calcd for C20H25F2NO3 [M]þ 365.1797; found
[365.1806].
4.6.7. 3-(1-Fluoro-1-methylethyl)-6,8-difluoro-4-(N-Boc-methyl-
aminoethynyl)chromane 8h. Following the general procedure the
title compound was isolated as a yellow oil (0.18 g, 52%): Rf 0.45
(ethyl acetate/hexane 3:7); vmax (NaCl)/cmꢁ1 (thin film) 3445,
3248, 2922, 2218,1686, 1598, 1484; 1H NMR (400 MHz, CDCl3): 6.88
(dd, J¼8.6, 2.5 Hz, 1H, AreH), 6.74 (ddd, J¼10.8, 8.6, 3.0 Hz, 1H,
15. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923e2925.
16. The reactions were not conducted on the same scale however the reaction
conditions provided are optimised.