The Titanium-Mediated Double Reductive Cleavage of Cyclic Sulfonamides for the Synthesis of Aryl Pyrrolidines

Article abstract of DOI:10.1021/acs.joc.8b02827

Reduction of a range of benzo-fused cyclic sulfonamides has been accomplished using low-valent titanium. This operationally simple method generates the corresponding aryl-substituted cyclic amines, typically, with good conversion. Notably, unlike our previous Li-NH₃-based method, loss of heteroatom-based substituents (X) on the aromatic ring does not readily occur, and the robustness of this method was demonstrated with a synthesis of the Sceletium alkaloid mesembrane.

Full text of DOI:10.1021/acs.joc.8b02827

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Note
The Titanium-Mediated Double Reductive Cleavage of
Cyclic Sulfonamides for the Synthesis of Aryl Pyrrolidines
Aisha Khalifa, and Paul Evans
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02827 • Publication Date (Web): 25 Jan 2019
Downloaded from http://pubs.acs.org on January 29, 2019
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The Titanium-Mediated Double Reductive Cleavage of Cyclic Sulfonamides for
the Synthesis of Aryl Pyrrolidines
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8
Aisha Khalifa and Paul Evans*
9
School of Chemistry, Centre for Synthesis and Chemical Biology, University College Dublin, Dublin D04,
N2E5, Ireland. Email: paul.evans@ucd.ie; ORCID: 0000-0002-0584-876X
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X
R
X
(1) Ti(IV), Mg
(2) TsCl
16 examples
0%-quant.
R
N
S
N
O2
Ts
Abstract-Reduction of a range of benzo-fused cyclic sulfonamides has been accomplished using low-
valent titanium. This operationally simple method generates the corresponding aryl substituted cyclic
amines, typically, with good conversion. Notably, unlike our previous Li-NH3-based method, loss of
heteroatom-based substituents (X) on the aromatic ring does not readily occur and the robustness of
this method was demonstrated with a synthesis of the Sceletium alkaloid mesembrane.
Keywords-sulfonamide, sultam, aryl amine, reduction, low-valent titanium
Introduction
The sulfonamide represents a useful functional group. It is an integral part of several pharmaceuticals
and is used in the design of biologically active compounds more generally. It also occupies a niche in
synthetic organic chemistry as a chemically robust nitrogen protecting group.1 In this context the fate
of the sulfonyl portion of the protecting group has, typically, been ignored, since the amino group
represents the portion of interest. However, several years ago our group speculated that, if a cyclic
sulfonamide of the type 1 was employed, a double reductive excision of the sulfonyl group might
produce an aryl amine of the type 2 (see Scheme 1).2 Compounds of type 1 can be formed from RCM
derived dihydropyrroles 3, via a reductive intramolecular Heck reaction sequence.3 Furthermore,
where applicable (R’  H), we have shown that this carbon-carbon bond forming process favours
generation of the more sterically encumbered quaternary product.3,4 Overall, we felt that the
sequence 3  2, featuring a traceless N-protecting group which facilitates the formation of an sp2-sp3
carbon-carbon bond (that may be quaternary), constitutes an efficient and attractive means for the
construction of aryl amines (2).
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R
R'
R'
(1) Li, NH3
(2) H
R
N
H
N
S
H
2
O2
1
OMe
OMe
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R'
Br
R
N
O
S
4
(+)-
O2
N
3
H
Me
Scheme 1. The “double” reduction of cyclic sulfonamides (1) to access aryl pyrrolidines (2).
Apart from the novel sulfonyl excision aryl amines themselves are also of interest. They are a motif
present in a variety of natural products and pharmaceutical agents, and we have applied the strategy
outlined in Scheme 1 for the synthesis of members of the Sceletium alkaloid family (eg. 4).5 In this
work we used Li (or Na) in liquid ammonia2 to achieve the key sulfonyl excision.6 Apart from the
relative inconvenience associated with the use of ammonia gas, one issue with this method is that if
a methoxy group is positioned para- to the sulfonyl moiety it is partially lost (group highlighted with a
box in structure 4, Scheme 1).2,5,7 As a consequence we were keen to investigate alternative reaction
conditions for this type of process. Among the several alternative methods available for the reductive
cleavage of sulfonamides8 we were attracted to the low-valent titanium technique reported in 2011
by Okamoto.9 In this work it was shown that alkyl and aryl sulfonamides undergo cleavage by an
undefined low-valent titanium species10 produced by the in situ reduction of Ti(IV) with Mg. In one
example from this work the fate of the aromatic portion was also considered. From this it was evident
that, during reaction of 5, reductive cleavage of both the N-S and the C-S bonds had taken place to
produce 6 in addition to expected secondary amine 7 (Scheme 2).9
(1) Ti(Oi-Pr)4,
TMSCl, Mg,
i-Pr
i-Pr
NBn2
i-Pr
i-Pr
H NBn2
+
S
H
THF, 50 °C
(2) Work-up
O2
i-Pr
i-Pr
7
: 93%
5
6
: 99%
Scheme 2. Okamoto’s low-valent titanium-based sulfonamide reduction.9
Results and Discussion
In order to study whether the low-valent titanium method successfully converted our cyclic
sulfonamides into aryl amines, compound 8a was selected (Table 1). Previously we reported2 that use
of Li in liquid NH3 produced a mixture of di- and mono-methoxy-substituted aryl amines, which in
order to purify and characterize, were converted into their N-tosyl sulfonamides.
Table 1. The reduction of dimethoxy-containing cyclic sulfonamide 8a.
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OMe
H
MeO
(1) Conditions
MeO
MeO
MeO
N
S
(2) TsCl, Et3N,
DCM, rt, 5-15 h
O2
N
N
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8a
Ts
Ts
9a
9d
H
MeO
MeO
N
S
O2
10
Entry
Conditions
8a
9a
28%
20%
83-
9d
36%
-
-
12
2
Li (20 equiv.), NH3, -78 °C, 0.5 h then NH4Cl
Li (4 equiv.), C10H8 (4 equiv.), THF, -78 °C, 0.5 h
Ti(Oi-Pr)4 (1.1 equiv.), Mg (6 equiv.),
TMSCl (2 equiv.), THF, 80 °C, 15 h (under Ar)
Mg (35 equiv.), EtOH-THF (5:1), rt-55 °C, 18 h
-
-
-
3
100%
4
100%
-
-
Thus, as shown in Entry 1, 9a and 9d were isolated in 28% and 36% respectively. It is likely that the
regioselective partial loss of the methoxy-substituent highlighted stems from a Birch-type radical
anionic intermediate.11 This undergoes protonation (from NH3) and re-aromatisation via a species of
the type 10. Subsequent sulfonamide reduction then ultimately generates the mono-methoxy
compound 9d. Based on this hypothesis it was felt that if the reaction was performed under aprotic
conditions then perhaps the loss of the methoxy group would not occur. Therefore, the use of lithium
naphthalenide in THF (or DME) was considered. As shown in Entry 2, this did successfully negate the
formation of 9d, however, the yields of 9a were poor.
In contrast, when the low-valent titanium method was used9 we were delighted to find that 9a was
not only the sole product and that it was also produced in excellent yields (Entry 3). Optimal results
for this process were found when the process was conducted in a sealed reaction vessel under an
argon atmosphere. Entry 4 demonstrates that unlike the successful outcome of the reaction
combining Ti(IV) and Mg, the use of Mg alone in a mixture of EtOH or MeOH and THF (due to the poor
solubility of 8a in alcoholic solvents), with, or without sonication, was unsuccessful and only starting
material 8a was recovered.8h,12
Table 2. The titanium-mediated reduction of cyclic sulfonamides 8b-8o.
R
R'
R''
(1) "Ti"
R
R''
N
R'
S
O2
(2) TsCl
N
Ts
8b-8o
9b-9o
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Entry Substrate
R
R’
R’’
Producta
Yieldb
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7
8
9
1
2
3
8b
8c
8d
H
H
H
79%
N
Ts
9b
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MeO
OMe
H
H
H
89%
79%
N
Ts
9c
MeO
H
OMe
N
Ts
9d
O
O
4
5
8e
8f
OCH2O
H
H
74%
61%
N
Ts
9e
9f
Cl
Cl
H
N
Ts
H2N
6
7
8g
8i
NO2
H
H
H
H
28%
65%
N
S
O2
8h
SO2Me
N
S
O2
8b
8
8j
H
H
Me
83%
N
Ts
9j
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MeO
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6
MeO
9
8k
OMe
OMe
Me
76%
7
8
9
N
Ts
9k
9l
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MeO
10
11
12
8l
8m
8n
OMe
H
H
Me
85%
80%
60%
N
Ts
H
i-C3H5
i-C3H5
N
Ts
9m
MeO
MeO
OMe
OMe
N
Ts
9n
9o
MeO
MeO
13
8o
OMe
OMe
i-Pr
62%
N
Ts
aConditions: (1) Ti(i-OPr)4 (1.1 equiv.), Mg (6.0 equiv.), TMSCl (2.0 equiv.), THF, 80 °C (oil bath
temperature), 15 h, under Ar; (2) TsCl, Et3N, DCM, rt, 15 h; bYields obtained after purification by flash
column chromatography.
In the light of the success with the low-valent titanium method a range of alternative examples bearing
different aromatic (R and R’) and benzylic (R’’) substituents were considered (Table 2). Substrates 8b-
8o were prepared according to our previously reported3 Heck-hydrogenation sequence and applying
the conditions outlined in Table 1 above their behaviour in the presence of low valent titanium was
evaluated. As shown in Table 2, Entry 1, the unsubstituted cyclic amide 8b smoothly gave 9b in a yield
comparable to the Li-NH3 method.2 Regioisomeric methoxy substituted cyclic sulfonamides 8c and 8d
and 1,3-dioxolane 8e were next considered (Entries 2-4). Again, in these examples, no loss of the
oxygen-based substituents was detected and the 3-aryl pyrrolidines 9c-9e were isolated in good yields.
In Okamoto’s original report one example of an aryl chloride-containing sulfonamide was included,
and the chloride unit survived the reaction. Based on this finding we were keen to evaluate how
sulfonamide 8f, containing a 4-chloro substituent, behaved. As shown in Entry 5 the chloro group
para-to the sulfonyl unit did indeed survive the reduction process and 9f was isolated in reasonable
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yield. Partly this outcome is notable because one might expect the aromatisation of an intermediate
resembling 10 (Table 1) to readily occur and then because 6 equiv. of Mg are present one might also
anticipate that competitive aryl magnesium reagent formation (either from 8f, or the pyrrolidine
product) might ensue over the course of the reaction. Next substrate 8g was considered in which a
nitro substituent is positioned para- to the sulfonyl group (Entry 6). In this case the nitro group does
not survive the reduction process and the corresponding aniline (R = NH2) was produced and isolated
in a low yield. In this case, under the standard reaction conditions (i.e. 1.1 equiv. of Ti(IV) etc.),
additional sulfonamide reduction was not clearly detected. Following the trend of positioning a
potentially reactive moiety para- to the sulfonamide unit, sulfone 8i was studied. This compound,
prepared by nucleophilic aromatic substitution using nitro sulfonamide 8g, underwent C-S sulfone
bond cleavage and not the desired sulfonamide reduction (Entry 7). Interestingly, under the reaction
conditions employed the resultant sulfonamide does not undergo further reaction to form the
pyrrolidine and 8b was isolated in 65% yield. Again, in this case the use of more equivalents of Ti(IV)
was not studied. In the final set of examples we incorporated a substituent into the R’’ position taking
advantage of the high degree of regioselectivity3,4 that can be obtained for intramolecular Heck
reactions of trisubstituted dihydropyrroles of the type 3 (Scheme 1). As Entries 8-13 indicate, in all
cases reasonable to good yields of the resultant pyrrolidine compounds, 9j-9o were obtained. The
unsaturated isopropenyl substitutent (R’’ = i-C3H5) deserves mention because in these cases (Entries
11 and 12) the alkene does not react competitively and does not interfere with the overall sulfonamide
reduction process and 9m and 9n were isolated in good to reasonable yield. Saturated isopropyl
derivative 8o also gave the product of double reduction 9o without event.
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Another interesting observation associated with chemoselectivity in Okamoto’s original report is that
benzylic bonds are not reductively cleaved under the low-valent titanium reaction conditions (see
formation of 7 in Scheme 2).9 Therefore, compound 11,2 an isomer of the 3-aryl cyclic sulfonamide
8b, was subjected to the titanium reduction under the standard conditions outlined in Tables 1 and 2.
As shown in Scheme 3, this was converted smoothly into 2-phenylpyrrolidine 12, with none of the
product of a further benzylic reduction detected. The additional benzylic reduction was observed
when an excess of Li in liquid NH3 was used, ultimately producing 13. 2
(1) "Ti"
NHTs
N
N
Ts
S
(2) TsCl
13
O2
12
11
: 78%
Scheme 3. The formation of 2-phenylpyrrolidine 12 from cyclic sulfonamide 11.
The finding that the methoxy group para- to the sulfonyl group does not undergo cleavage during the
titanium-mediated process (Tables 1 and 2) encouraged us to re-visit our syntheses of the Sceletium
alkaloids, of which mesembrane (16) is a representative member. Thus, racemic cyclic sulfonamide
144 was converted in reasonably good yield to carbamate protected octahydroindole 15 with no
evidence of any loss of the methoxy-substituent highlighted (Scheme 4). This then gave racemic
mesembrane 16 in a considerably more efficient overall sequence than that achieved previously with
Li-NH3 – which was hampered by the partial loss of the methoxy group highlighted.
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MeO
MeO
OMe
OMe
5
6
7
8
9
(1) "Ti"
(2) CbzCl
MeO
MeO
LAH
H
N
S
N
N
10
11
12
13
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H
H
O2
Me
Cbz
14
15
16
: 66%
: 81%
Scheme 4. The synthesis of mesembrane 16 by reduction of cyclic sulfonamide 14.
In summary, we have shown that low-valent titanium sulfonamide reduction can be effectively applied
to a range of benzo-fused cyclic sulfonamides. In this process the sulfonyl group is excised and the
N-S and C-S bonds are converted into N-H and C-H bonds respectively. We have shown that this
method is generally applicable and can tolerate a range of different aromatic (R and R’) and benzylic
(R’’) substituents. Substrates were selected in which a potential leaving group/reactive group (R =
OMe, Cl, NO2, SO2Me) is located para- to the sulfonyl group and only in the case of the nitro and
sulfone substituted compounds, 8g and 8i was competitive reaction, during the hoped for sulfonamide
cleavage, observed. Unsaturation in the shape of a benzylic isopropenyl group (8m and 8n), was
unchanged over the course of the sulfonamide reduction and substrate 11, with a potentially reactive
benzylic C-N bond, gave only the hoped for sulfonamide cleavage process. Finally, the synthesis of
mesembrane 16, without loss of the vulnerable ether substituents, demonstrates the improvement
of the described method for the double reduction of cyclic sulfonamides over the alternative Li, or Na-
NH3 method.
Experimental Section
General directions: Reagents from commercial suppliers were used without further purification and
anhydrous DMF. H and H-decoupled 13C NMR spectra were recorded on a Varian Unity 400 MHz
spectrometer and coupling constants (J) are quoted in Hertz. All values are reported in ppm and were
referenced to either tetramethylsilane or residual protonated chloroform. Assignment was aided by
two-dimensional NMR (g-COSY and HSCQ). High resolution mass spectra were carried out on a VG
analytical 70-E mass spectrometer under electrospray ionisation conditions (ESI) and a time-of-flight
(TOF) analyser. Infrared spectra were recorded on a Bruker Alpha FTIR spectrometer. Melting points
were recorded on a Gallenkamp electrothermal melting point apparatus. Thin-layer chromatography
was performed on silica coated aluminium sheets and compounds were visualized with UV light and
aqueous potassium permanganate, followed by heating. Merck silica gel (0.040-0.063 mm) was used
for the flash column chromatography. The preparation of compounds 8a-g,3b 8j-n,3b 112 and 144a were
performed according to literature procedures.
1
1
General procedure for the Ti-based preparation and isolation of aryl pyrrolidines from cyclic
sulfonamides: Under argon in oven-dry glassware the unsaturated sulfonamide substrate (0.185
mmol, 1 equiv.) was dissolved in anhydrous THF (3 mL). The solution was degassed under a steady
flow of argon (ca. 10 min). Mg powder (6 equiv.) [activated by heating at 80°C for 30 min under Ar],
Ti(Oi-Pr)4 (1.1 equiv.) and Me3SiCl (2 equiv.) were added sequentially. After approx. 0.5 h the mixture
turned black and was heated with stirring at 80 -100 °C (oil bath temperature) for 15 h. TLC analysis
can be used to judge reaction completion. After cooling to room temperature, aqueous 1 M NaOH
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(0.4 mL), Et2O (15 mL), anhydrous NaF (1.0 g) and Celite (1.0 g) were sequentially added. The mixture
was stirred for 30 min, decanted and the residue washed with Et2O (3 x 15 mL) [alternatively, this
mixture can be filtered through a Celite pad, washing with Et2O (2 x 15 mL)]. After initial extraction
the resultant aqueous phase was re-extracted with Et2O (3 x 15 mL) and the organic extracts were
combined. Drying over MgSO4, followed by filtration and solvent removal gave the crude amine. A
solution of the crude amine in CH2Cl2 (10 mL) was treated with triethylamine (0.39 mmol, 2 equiv.)
and p-TsCl (0.204 mmol, 1.1 equiv.) at 0 °C. Stirring was continued for 15 h and the reaction gradually
warmed to room temperature. Silica (ca. 2.0 g) was added to the reaction mixture and the solvent was
removed under reduced pressure. Purification by flash column chromatography afforded the desired
reduced cyclic amine.
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3-(3,4-Dimethoxyphenyl)-1-tosylpyrrolidine 9a: Under argon gas, to a mixture of alkane 8a (50 mg,
0.185 mmol, 1 equiv.) and Mg powder (31 mg, 1.28 mmol, 7 equiv.) in THF (3 mL) was added Ti(Oi-Pr)4
(0.060 mL, 0.203 mmol, 1.1 equiv.) and Me3SiCl (0.052 mL, 0.410 mmol, 2.2 equiv.). The resulting
mixture was stirred at 80 °C (oil bath temperature) for 15 h. Aqueous 1 M NaOH (0.4 mL), Et2O (15
mL), anhydrous NaF (1.0 g) and Celite (1.0 g) were added at room temperature. After stirring for 30
min, the mixture was filtered through a pad of Celite. To the resulting filtrate was added aqueous 1 M
NaOH (15 mL) and the mixture was extracted with Et2O (15 mL). The organic layer was washed with
aqueous 1 M NaOH (0.4 mL) and dried over anhydrous Na2SO4. Filtration followed by solvent removal
under reduced pressure afforded the crude amine. A solution of the crude amine in CH2Cl2 (10 mL)
was treated with triethylamine (0.057 mL, 0.41 mmol, 2.2 equiv.) and p-TsCl (46 mg, 0.24 mmol, 1.3
equiv.) at 0 °C. Stirring was continued for 15 h and the reaction gradually warmed to room
temperature. Silica (ca. 2.0 g) was added to the reaction mixture and solvent removal under pressure.
Purification by flash column chromatography (c-Hex-EtOAc; 2:1) gave 9d (67 mg, 100 %) as a tan
colored viscous oil. Rf = 0.5 (c-Hex-EtOAc; 1:1); 1H-NMR (400 MHz, CDCl3) δ = 1.81-1.91 (1H, m, CH2),
2.15-2.23 (1H, m, CH2), 2.46 (3H, s, CH3), 3.15-3.24 (2H, m, CH, CH2), 3.31-3.37 (1H, m, CH2), 3.53-3.59
(1H, m, CH2), 3.66-3.75 (1H, m, CH2), 3.83 (3H, s, CH3), 3.84 (3H, s, CH3), 6.64 (1H, s, ArH), 6.66 (1H, d,
J = 8.0 Hz, ArH), 6.76 (1H, d, J = 8.0 Hz, ArH), 7.34 (2H, d, J = 8.0 Hz, ArH), 7.76 (2H, d, J = 8.0 Hz, ArH)
ppm; 13C{1H}-NMR (100 MHz, CDCl3) δ = 21.5 (CH3), 33.0 (CH2), 43.8 (CH), 47.8 (CH2), 54.1 (CH2), 55.8
(CH3), 55.85 (CH3), 110.1 (CH), 111.1 (CH), 118.8 (CH), 127.5 (CH), 129.6 (CH), 133.1 (C), 133.9 (C), 143.4
(C), 147.9 (C), 148.9 (C) ppm. Data consistent with literature.2
3-Phenyl-1-tosylpyrrolidine 9b: Following the general procedure, 8b (50 mg, 0.24 mmol, 1 equiv.) was
converted into 9b. Purification by flash column chromatography (c-Hex-EtOAc; 3:1) gave of 5b (57 mg,
79 %) as a colorless solid. M.p. 65 C; Rf = 0.3 (c-Hex-EtOAc; 3:1). 1H-NMR (400 MHz, CDCl3) δ = 1.82-
1.94 (1H, m, CH2), 2.17-2.25 (1H, m, CH2), 2.46 (3H, s, CH3), 3.18-3.29 (2H, m, CH, CH2), 3.37 (1H, dd, J
= 10.0, 7.0 Hz, CH2), 3.54 (1H, ddd, J = 10.0, 8.5, 3.5 Hz, CH2), 3.70-3.78 (1H, m, CH2), 7.11 (2H, d, J =
7.0 Hz, ArH), 7.18-7.30 (3H, m, ArH), 7.35 (2H, d, J = 8.0 Hz, ArH), 7.77 (2H, d, J = 8.0 Hz, ArH) ppm;
13C{1H}-NMR (100 MHz, CDCl3) δ = 21.5 (CH3), 32.9 (CH2), 43.8 (CH), 47.8 (CH2), 54.1 (CH2), 126.9 (CH),
126.95 (CH), 127.6 (CH), 128.6 (CH), 129.7 (CH), 134.1 (C), 140.7 (C), 143.4 (C) ppm. Data consistent
with literature.2
3-(3-Methoxyphenyl)-1-tosylpyrrolidine 9c: Following the general procedure, 8c (50 mg, 0.21 mmol,
1 equiv.) was converted into 9c. Silica (ca. 2.0 g) was added to the reaction mixture and solvent
removal under pressure. Purification by flash column chromatography (c-Hex-EtOAc; 2:1) gave 9c (61
푣
mg, 89 %) as a tan colored viscous oil. Rf = 0.6 (c-Hex-EtOAc; 1:1); max 2921, 2889, 2834, 1930, 1726,
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1595, 1493, 1464, 1453, 1430, 1336, 1287, 1257, 1152, 1111, 1028, 1014, 966, 845, 818, 783, 757,
692, 660, 587, 546, 511, 457 cm-1; 1H-NMR (400 MHz, CDCl3) δ = 1.78-1.89 (1H, m, CH2), 2.15-2.23 (1H,
m, CH2), 2.47 (3H, s, CH3), 3.13-3.25 (2H, m, CH, CH2), 3.32-3.40 (1H, m, CH2), 3.51-3.57 (1H, m, CH2),
3.69-3.74 (1H, m, CH2), 3.77 (3H, s, CH3), 6.65-6.63 (1H, m, ArH), 6.67 (1H, d, J = 7.5 Hz, ArH), 6.75 (1H,
dd, J = 7.5, 1.5 Hz, ArH), 7.18 (1H, t, J = 7.5 Hz, ArH), 7.34 (2H, d, J = 8.0 Hz, ArH), 7.75 (2H, d, J = 8.0
Hz, ArH), ppm; 13C{1H}-NMR (100 MHz, CDCl3) δ = 21.6 (CH3), 33.2 (CH2), 44.2 (CH), 48.2 (CH2), 54.4
(CH2), 55.6 (CH3), 112.3 (CH), 113.4 (CH), 119.6 (CH), 127.9 (CH), 130.1 (CH), 130.1 (CH), 134.1 (C),
142.6 (C), 143.8 (C), 160.1 (C) ppm; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C18H22NO3S 332.1320;
Found 332.1305.
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3-(4-Methoxyphenyl)-1-tosylpyrrolidine 9d: Following the general procedure, 8d (50 mg, 0.21 mmol,
1 equiv.) was converted into 9d. Purification by flash column chromatography (c-Hex-EtOAc; 2:1) gave
푣
9d (55 mg, 79 %) as a yellow colored viscous oil. Rf = 0.15 (c-Hex-EtOAc; 4:1); max 3054, 2958, 2927,
1599, 1492, 1454, 1436, 1340, 1264, 1157, 816, 780, 731, 699, 661, 590, 547 cm-1. 1H-NMR (400 MHz,
CDCl3) δ = 1.78-1.89 (1H, m, CH2), 2.15-2.23 (1H, m, CH2), 2.47 (3H, s, CH3), 3.13-3.25 (2H, m, CH, CH2),
3.32-3.40 (1H, m, CH2), 3.51-3.57 (1H, m, CH2), 3.69-3.74 (1H, m, CH2), 3.80 (3H, s, CH3), 6.83 (2H, d, J
= 8.0 Hz, ArH), 7.05 (2H, d, J = 8.0 Hz, ArH), 7.37 (2H, d, J = 8.0 Hz, ArH), 7.78 (2H, d, J = 8.0 Hz, ArH)
ppm; 13C{1H}-NMR (100 MHz, CDCl3) δ = 21.6 (CH3), 33.2 (CH2), 43.2 (CH), 47.8 (CH2), 54.4 (CH2), 55.2
(CH3), 113.9 (CH), 127.5 (CH), 127.9 (CH), 129.7 (CH), 132.5 (C), 133.8 (C), 143.4 (C), 158.4 (C) ppm.
Data consistent with literature.2
3-(Benzo[d][1,3]dioxol-5-yl)-1-tosylpyrrolidine 9e: Following the general procedure alkane 8e (50
mg, 0.197 mmol, 1 equiv.) was converted into 9e which after conversion of the intermediate amine
was purified by flash column chromatography (c-Hex-EtOAc; 2:1). This gave 9e (50 mg, 74 %) as white
푣
max
solid. M.p. 100-103 °C; Rf = 0.6 (c-Hex-EtOAc; 2:1);
2944, 2858, 2848, 1698, 1596, 1503, 1488,
1234, 1159, 1126, 1038, 785, 672, 589, 569 cm-1; 1H-NMR (400 MHz, CDCl3) δ = 1.76-1.86 (1H, m, CH2),
2.13-2.21 (1H, m, CH2), 2.48 (3H, s, CH3), 3.09-3.20 (2H, m, CH, CH2), 3.30-3.35 (1H, m, CH2), 3.49-3.52
(1H, m, CH2), 3.66-3.72 (1H, m, CH2), 5.94 (2H, s, CH2), 6.55 (1H, s, ArH), 6.57 (1H, d, J = 7.5 Hz, ArH),
6.71 (1H, d, J = 7.5 Hz, ArH), 7.36 (2H, d, J = 8.0 Hz, ArH), 7.76 (2H, d, J = 8.0 Hz, ArH) ppm; 13C{1H}-NMR
(100 MHz, CDCl3) δ = 21.1 (CH3), 33.0 (CH2), 43.9 (CH), 48.0 (CH2), 54.1 (CH2), 101.2 (CH2), 107.4 (CH),
108.4 (CH), 120.2 (CH), 127.4 (CH), 129.8 (CH), 134.0 (C), 134.7 (C), 143.7 (C), 146.6 (C), 148.0 (C) ppm;
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C18H20NO4S 346.1113; Found 346.1107.
3-(3-Chlorophenyl)-1-tosylpyrrolidine 9f: Following the general procedure, 8f (50 mg, 0.21 mmol, 1
equiv.) was converted into 9f. Purification by flash column chromatography (c-Hex-EtOAc; 6:1) gave
푣
9f (43 mg, 61 %) as a pale viscous oil. Rf = 0.15 (c-Hex-EtOAc; 6:1); max 3054, 2984, 2971, 2901, 1597,
1572, 1480, 1344, 1264, 1160, 1046, 895, 731, 703, 662, 591, 549 cm-1; 1H-NMR (400 MHz, CDCl3) δ =
1.78-1.89 (1H, m, CH2), 2.15-2.23 (1H, m, CH2), 2.47 (3H, s, CH3), 3.13-3.25 (2H, m, CH, CH2), 3.32-3.40
(1H, m, CH2), 3.51-3.57 (1H, m, CH2), 3.69-3.74 (1H, m, CH2), 6.99-7.03 (1H, m, ArH), 7.05 (1H, s, ArH),
7.18-7.23 (2H, m, ArH), 7.35 (2H, d, J = 8.0 Hz, ArH), 7.75 (2H, d, J = 8.0 Hz, ArH) ppm; 13C{1H}-NMR
(100 MHz, CDCl3) δ = 21.6 (CH3), 32.9 (CH2), 43.3 (CH), 47.5 (CH2), 53.0 (CH2), 125.1 (CH), 126.9 (CH),
127.3 (CH), 127.6 (CH), 129.6 (CH), 129.9 (CH), 133.5 (C), 134.2 (C), 142.7 (C), 143.4 (C) ppm; HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C17H19NO2S35Cl 336.0825; Found 336.0840.
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4-Amino-8-thia-9-aza-tricyclo[7.2.1.02,7]dodeca-2(7),3,5-triene 8,8-dioxide 8h: Following the general
procedure 8g (50 mg, 0.19 mmol, 1 equiv.) gave aniline 8h (12 mg, 28%) with data corresponding to
literature.3b
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4-(Methylsulfonyl)-8-thia-9-aza-tricyclo[7.2.1.02,7]dodeca-2(7),3,5-triene 8,8-dioxide 8i: A solution
of 4-nitro sulfonamide 8g3b (116 mg, 0.46 mmol, 1 equiv.) in anhydrous DMF (4 mL) was treated with
NaSMe (60 mg, 0.86 mmol, 1.9 equiv.). Stirring was continued at room temperature for 18 h before
the mixture was diluted with water (15 mL) and extracted with EtOAc (2 x 15 mL). The combined
organic extracts were dried over MgSO4, filtered and the solvent removed under reduced pressure.
Purification by flash column chromatography (c-Hex-EtOAc; 3:1 to 1:1) gave 4-(methylthia)-8-thia-9-
aza-tricyclo[7.2.1.02,7]dodeca-2(7),3,5-triene 8,8-dioxide (80 mg, 68 %) as a viscous oil [Rf = 0.15 (c-
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Hex-EtOAc; 3:1); max 3045, 2966, 2899, 1584, 1328, 1295, 1163, 1107, 920 cm-1; 1H-NMR (400 MHz,
푣
CDCl3) δ = 1.88-1.98 (1H, m, CH2), 2.20-2.31 (1H, m, CH2), 2.48 (3H, s, CH3), 3.16-3.23 (2H, m, CH, CH2),
3.48 (1H, ddd, J = 14.5, 10.5, 4.0 Hz, CH2), 3.82-3.90 (1H, m, CH2), 4.23 (1H, d, J = 12.5 Hz, CH2), 7.02
(1H, d, J = 1.5 Hz, ArH), 7.18 (1H, dd, J = 8.5, 1.5 Hz, ArH), 7.65 (1H, d, J = 8.5 Hz, ArH), ppm; 13C{1H}-
NMR (100 MHz, CDCl3) δ = 14.9 (CH3), 33.1 (CH2), 39.8 (CH), 46.8 (CH2), 56.9 (CH2), 123.5 (CH), 125.1
(CH), 126.5 (CH), 131.4 (C), 141.3 (C), 145.2 (C) ppm; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C11H14NO2S2 256.0466; Found 256.0473]. Oxone® (1.00 g, 1.63 mmol, 5.3 equiv.) was added in one
portion to a solution of the above sulfide (80 mg, 0.31 mmol, 1 equiv.) in MeOH (15 mL). Stirring was
maintained for 2 days at rt. At this point most of the solvent was removed under reduced pressure
and water (25 mL) and DCM (15 mL) were added. The resultant aqueous layer was further extracted
with DCM (2 x 15 mL) and the combined organic extracts were dried over MgSO4. After filtration and
solvent removal under reduced pressure the crystalline residue was purified by gradient elution flash
column chromatography (c-Hex-EtOAc; 3:1 to 1:3) to afford 8i (84 mg, 94 %) as a colorless crystalline
푣
solid. Rf = 0.25 (c-Hex-EtOAc; 1:3); M.p = 198-200 °C; max 3073, 3020, 2932, 1402, 1327, 1312, 1297,
1161, 1095, 969 cm-1; H-NMR (400 MHz, CDCl3) δ = 1.94- 2.02 (1H, m, CH2), 2.29-2.38 (1H, m, CH2),
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3.06 (3H, s, CH3), 3.28 (1H, dd, J = 13.0, 3.0 Hz, CH2), 3.42 (1H, dd, J = 6.5, 3.0 Hz, CH), 3.55 (1H, ddd, J
= 14.5, 10.5, 4.0 Hz, CH2), 3.84-3.92 (1H, m, CH2), 4.28 (1H, d, J = 13.0 Hz, CH2), 7.84 (1H, d, J = 1.5 Hz,
ArH), 7.94 (1H, dd, J = 8.0, 1.5 Hz, ArH), 7.99 (1H, d, J = 8.0 Hz, ArH) ppm; 13C{1H}-NMR (100 MHz, CDCl3)
δ = 32.9 (CH2), 39.7 (CH), 44.3 (CH3), 46.7 (CH2), 56.9 (CH2), 126.6 (CH), 127.3 (CH), 127.9 (CH), 140.8
(C), 142.5 (C), 144.0 (C) ppm; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C11H14NO4S2 288.0364; Found
288.0372; C11H13NO4S2 Requires C: 45.98, H: 4.56, N: 4.87%; Found C: 46.21, H: 4.55, N: 4.62%.
8-Thia-9-azatricyclo[7.2.1.02,7]dodeca-2(7),3,5-triene-8,8-dioxide 8b: Following the general
procedure, 8i (50 mg, 0.17 mmol, 1 equiv.) was converted into 8b. Purification by flash column
chromatography (c-Hex-EtOAc; 3:1) gave 8b (23 mg, 65 %), which was isolated as a colorless crystalline
solid. M.p. = 120-122°C; Rf = 0.4 (c-Hex-EtOAc; 1:1). Data corresponds to that previously reported.2,3
3-Methyl-3-phenyl-1-tosylpyrrolidine 9j: Following the general procedure alkane 8j (50 mg, 0.22
mmol, 1 equiv.) converted to 9j following purification by flash chromatography (c-Hex-EtOAc; 3:1)
푣
max
gave of 9j (59 mg, 83 %) as a colorless oil. Rf = 0.4 (c-Hex-EtOAc; 3:1);
2965, 2876, 1597, 1496,
1445, 1343, 1158, 1095, 663 cm-1; 1H-NMR (400 MHz, CDCl3) δ = 1.20 (3H, s, CH3), 1.96-2.10 (2H, m,
CH2), 2.41 (3H, s, CH3), 3.39 (1H, d, J = 9.5 Hz, CH2), 3.39-3.50 (2H, m, CH2), 3.55 (1H, d, J = 9.5 Hz, CH2),
7.14 (2H, d, J = 7.0 Hz, ArH), 7.20-7.22 (1H, m, ArH), 7.24-7.32 (4H, m, ArH), 7.73 (2H, d, J = 8.0 Hz,
ArH) ppm; 13C{1H}-NMR (100 MHz, CDCl3) δ = 21.4 (CH3), 27.7 (CH3), 37.6 (CH2), 45.9 (C), 46.5 (CH2),
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58.9 (CH2), 125.9 (CH), 126.5 (CH), 127.6 (CH), 128.6 (CH), 129.7 (CH), 134.1 (C), 143.4 (C) 146.4 (C)
ppm; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C18H22NO2S 316.1371; Found 316.1366.
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3-(3,4-Dimethoxyphenyl)-3-methyl-1-tosylpyrrolidine 9k: As per the general procedure, a mixture of
alkane 8k (50 mg, 0.176 mmol, 1 equiv.) yielded 9k (50 mg, 76 %) as a white solid following purification
푣
max
by flash column chromatography (c-Hex-EtOAc; 2:1). M.p. = 94-98 °C; Rf = 0.4 (c-Hex-EtOAc; 2:1);
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2960, 2917, 1520, 1464, 1340, 1255, 1158, 1094, 1027, 807, 663 cm-1; 1H-NMR (400 MHz, CDCl3) δ =
1.19 (3H, s, CH3), 1.90-2.12 (2H, m, CH2), 2.46 (3H, s, CH3), 3.51-3.39 (4H, m, CH2), 3.83 (3H, s, CH3),
3.84 (3H, s, CH3), 6.66-6.70 (2H, m, ArH), 6.76 (1H, d, J = 8.0 Hz, ArH), 7.30 (2H, d, J = 8.0 Hz, ArH), 7.76
(2H, d, J = 8.0 Hz, ArH) ppm; 13C{1H}-NMR (100 MHz, CDCl3) δ = 21.5 (CH3), 27.6 (CH3), 37.8 (CH2), 45.7
(C), 46.6 (CH2), 55.9 (CH3), 55.95 (CH3), 59.2 (CH2), 109.3 (CH), 111.1 (CH), 117.5 (CH), 127.4 (CH), 129.6
(CH), 134.3 (C), 139.0 (C), 143.3 (C), 147.7 (C), 148.9 (C) ppm; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C20H26NO4S 376.1583; Found 376.1590.
3-(3-Methoxyphenyl)-3-methyl-1-tosylpyrrolidine 9l: Following the general procedure, alkane 8l (50
mg, 0.197 mmol, 1 equiv.) yielded 9l (58 mg, 85 %) as a viscous oil after purification by flash column
푣
chromatography (c-Hex-EtOAc; 6:1). Rf = 0.25 (c-Hex-EtOAc; 6:1); max 2961, 2924, 2874, 2854, 1598,
1582, 1488, 1451, 1336, 1290, 1154, 1090, 1043, 925, 804, 783, 701, 661, 592, 546 cm-1; 1H-NMR (400
MHz, CDCl3) δ = 1.19 (3H, s, CH3), 1.94-2.03 (2H, m, CH2), 2.41 (3H, s, CH3), 3.30 (1H, d, J = 9.5 Hz, CH2),
3.34-3.41 (2H, m, CH2), 3.46 (1H, d, J = 9.5 Hz, CH2), 3.72 (3H, s, CH3), 6.61 (1H, s, ArH), 6.64-6.70 (1H,
m, ArH), 7.14 (1H, t, J = 7.5 Hz, ArH), 7.30 (2H, d, J = 8.0 Hz, ArH), 7.72 (2H, d, J = 8.0 Hz, ArH) ppm;
13C{1H}-NMR (100 MHz, CDCl3) δ = 21.6 (CH3), 27.3 (CH3), 37.4 (CH2), 45.9 (CH2), 46.5 (C), 55.2 (CH3),
58.3 (CH2), 111.1 (CH), 112.1 (CH), 117.8 (CH), 127.4 (CH), 129.5 (CH), 129.6 (CH), 134.1 (C), 143.3 (C),
148.0 (C), 159.6 (C) ppm; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C19H24NO3S 346.1477; Found
346.1461.
3-Phenyl-3-(prop-1-en-2-yl)-1-tosylpyrrolidine 9m: Following the general procedure, 8m (50 mg, 0.20
mmol, 1 equiv.) was converted into 9m. Purification of the crude reaction product by flash column
chromatography (c-Hex-EtOAc; 9:1) gave 9m (55 mg, 80 %) as viscous oil. Rf = 0.45 (c-Hex-EtOAc; 3:1);
푣max
3055, 3026, 2922, 2853, 1642, 1597, 1493, 1446, 1341, 1160, 1091, 1053, 898, 815, 763, 735, 700,
663, 599, 547 cm-1; 1H-NMR (400 MHz, CDCl3) δ = 1.57 (3H, s, CH3), 2.03-2.06 (1H, m, CH2), 2.16-2.22
(1H, m, CH2), 2.42 (3H, s, CH3), 3.21-3.30 (1H, m, CH2), 3.40-3.47 (1H, m, CH2), 3.57 (1H, d, J = 9.5 Hz,
CH2), 3.69 (1H, d, J = 9.5 Hz, CH2), 4.87 (1H, s, CH2), 4.93 (1H, s, CH2), 7.14-7.32 (5H, m, ArH), 7.29 (2H,
d, J = 8.0 Hz, ArH), 7.70 (2H, d, J = 8.0 Hz, ArH) ppm; 13C{1H}-NMR (100 MHz, CDCl3) δ = 20.7 (CH3), 21.6
(CH3), 35.5 (CH2), 46.7 (C), 55.8 (CH2), 56.0 (CH2), 110.7 (CH2), 126.1 (CH), 126.5 (CH), 127.1 (CH), 128.2
(CH), 129.5 (CH), 135.1 (C), 142.9 (C), 143.7 (C), 147.3 (C) ppm; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd
for C20H23NO2NaS 364.1347; Found 364.1331.
3-(3,4-Dimethoxyphenyl)-3-(prop-1-en-2-yl)-1-tosylpyrrolidine 9n: Following the general procedure,
8n (39 mg, 0.126 mmol, 1 equiv.) was converted into 9n. Purification by flash column chromatography
(c-Hex-EtOAc; 6:1) gave 9n (30.5 mg, 60 %) as light tan colored viscous oil. Rf = 0.35 (c-Hex-EtOAc; 3:1);
2952, 2927, 2870, 1641, 1597, 1517, 1454, 1337, 1255, 1162, 1028, 814, 765, 664, 594, 548 cm-1;
푣max
1H-NMR (400 MHz, CDCl3) δ = 1.47 (3H, s, CH3), 1.94-2.04 (1H, m, CH2), 2.10-2.18 (1H, m, CH2), 2.42
(3H, s, CH3), 3.21-3.30 (1H, m, CH2), 3.40-3.46 (1H, m, CH2), 3.54 (1H, d, J = 9.5 Hz, CH2), 3.67 (1H, d, J
= 9.5 Hz, CH2), 3.82 (3H, s, CH3), 3.85 (3H, s, CH3), 4.88 (1H, s, CH2), 4.91 (1H, s, CH2), 6.66-6.73 (3H, m,
ArH), 7.28 (2H, d, J = 8.0 Hz, ArH), 7.69 (2H, d, J = 8.0 Hz, ArH) ppm; 13C{1H}-NMR (100 MHz, CDCl3) δ =
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20.2 (CH3), 21.4 (CH3), 35.1 (CH2), 46.2 (CH2), 54.9 (C), 55.6 (CH2), 55.7 (CH3), 55.75 (CH3), 109.8 (CH),
110.5 (CH), 110.55 (CH2), 118.3 (CH), 127.2 (CH), 129.4 (CH), 134.6 (C), 134.7 (C), 143.0 (C), 146.9 (C),
147.6 (C), 148.6 (C) ppm; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C22H27NO4NaS 424.1559; Found
424.1551.
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4,5-Dimethoxy-1-(prop-2-yl)-8-thia-9-azatricyclo[7.2.1.02,7]dodeca-2(7),3,5-triene 8,8-dioxide 8o:
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4,5-Dimethyoxy-1-(prop-1-en-2-yl)-8-thia-9-azatricyclo[7.2.1.02,7]dodeca-2(7),3,5,10-tetraene
8,8-
dioxide (65 mg, 0.021 mmol) was dissolved in EtOAc (12 mL). This solution (0.018 M) was pumped
(0.5 mL/min) through a ThalesNano H-cube® at ca. 13 Bar H2 pressure containing 10% w/w Pd/C in a
cartridge (70 x 4 mm) which was set to 30 °C. After one-pass the apparatus was washed through with
EtOAC (12 mL) and the solvent was removed under reduced pressure to afford 8n (65 mg, 99%) as a
white solid. Proton NMR spectroscopy indicated that this compound did not require additional
푣
purification. M.p. = 130-133 °C; Rf = 0.35 (c-Hex-EtOAc; 1:1); max 2959, 2923, 2849, 1712, 1599, 1566,
1506, 1463, 1443, 1323, 11304,1263, 1214, 1157, 1033, 985, 913, 864, 773, 713, 695, 666, 604, 526,
516 cm-1; 1H-NMR (400 MHz, CDCl3) δ = 1.02 (3H, d, J = 7.0 Hz,CH3), 1.15 (3H, d, J = 7.0 Hz, CH3), 1.63-
1.78 (1H, m, CH2), 2.18-2.30 (1H, m, CH2), 2.53-2.68 (1H, m, CH), 3.18 (1H, d, J = 12.5 Hz, CH2), 3.51-
3.59 (1H, m, CH2), 3.74 -3.84 (1H, m, CH2), 3.92 (6H, s, CH3), 4.08 (1H, d, J = 12.5 Hz, CH2), 6.85 (1H, s,
ArH), 7.25 (1H, s, ArH) ppm; 13C{1H}-NMR (100 MHz, CDCl3) δ = 17.2 (CH3), 20.5 (CH3), 28.4 (CH), 35.4
(CH2), 48.0 (CH2), 49.7 (C), 56.1 (CH3), 56.2 (CH2, CH3), 106.8 (CH), 108.0 (CH), 127.3 (C), 136.3 (C), 148.1
(C), 152.0 (C) ppm; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C15H21NO4NaS 334.1089; Found 334.1089.
3-(3,4-Dimethoxyphenyl)-3-(prop-2-yl)-1-tosylpyrrolidine 9o: Following the general procedure, 8o
(50 mg, 0.161 mmol, 1 equiv.) was converted into 9o. Purification of the crude reaction mixture by
flash column chromatography (c-Hex-EtOAc; 6:1) gave 9o (40 mg, 62 %) as a light brown colored
푣
max
viscous oil. Rf = 0.3 (c-Hex-EtOAc; 3:1);
3063, 2923, 2875, 2851, 2834, 1597, 1511, 1462, 1328,
1249, 1239, 1143, 1095, 1023, 812, 765, 734, 660, 592, 547 cm-1; 1H-NMR (400 MHz, CDCl3) δ = 0.72-
0.75 (6H, m, CH3), 1.76 (1H, sept, J = 7.0 Hz, CH), 2.07-2.13 (2H, m, CH2), 2.42 (3H, s, CH3), 3.16-3.22
(1H, m, CH2), 3.40-3.47 (1H, m, CH2), 3.55 (1H, d, J = 10.0 Hz, CH2), 3.58 (1H, d, J = 10.0 Hz, CH2), 3.82
(3H, s, CH3), 3.85 (3H, s, CH3), 6.56-6.61 (2H, m, ArH), 6.71 (1H, d, J = 8.0 Hz, ArH), 7.24 (2H, d, J = 8.0
Hz, ArH), 7.64 (2H, d, J = 8.0 Hz, ArH) ppm; 13C{1H}-NMR (100 MHz, CDCl3) δ = 18.2 (CH3), 18.6 (CH3),
21.3 (CH3), 33.9 (CH), 34.5 (CH2), 46.3 (CH2), 53.4 (C), 55.7 (CH3), 55.8 (CH3), 56.1 (CH2), 110.2 (CH),
111.3 (CH), 119.6 (CH), 127.3 (CH), 129.5 (CH), 133.2 (C), 134.2 (C), 142.9 (C), 147.0 (C), 148.0 (C) ppm;
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C22H30NO4S 404.1896; Found 404.1886.
2-Phenyl-1-tosylpyrrolidine 12: Following the general procedure, 11 (50 mg, 0.23 mmol, 1 equiv.)2
was converted into 12. Purification by flash column chromatography (c-Hex-EtOAc; 5:1) yielded 12
(54.5 mg, 78 %) as a colorless solid. M.p = 70 -74°C; Rf = 0.3 (c-Hex-EtOAc; 3:1); data corresponds to
that previously reported.2
2,3-Dimethoxy-7,8,9,10-tetrahydro-6aH-6,10a-ethanodibenzo[c,e][1,2]thiazine 5,5-dioxide 14: 2,3-
Dimethoxy-7,8,9,10-tetrahydro-6aH-6,10a-ethenodibenzo[c,e][1,2]thiazine 5,5-dioxide (140 mg,
0.044 mmol)4a was dissolved in EtOAc (15 mL). This solution (0.03 M) was then pumped (0.5 mL/min)
through a ThalesNano H-cube® at ca. 14 Bar H2 pressure containing 10% w/w Pd/C at a temperature
of 30 °C. Following the elution, the system was washed with EtOAc (15 mL) and the combined solvent
removed under reduced pressure. This afforded 14 (141 mg, quant) as a white solid with data that
corresponds to that previously reported.4a
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(±)-3a-(3,4-Dimethoxyphenyl)-1-methyloctahydroindole (mesembrane) 16: Following the first phase
of the general procedure, under argon gas a mixture of alkane 14 (100 mg, 0.31 mmol, 1 equiv.) and
Mg powder (45 mg, 1.86 mmol, 6 equiv.) in THF (6 mL) was treated with Ti(Oi-Pr)4 (0.1 mL, 0.34 mmol,
1.1 equiv.) and Me3SiCl (0.078 mL, 0.62 mmol, 2 equiv.). The resulting mixture was stirred at 80 °C for
15 h. Work up as described afforded the crude amine. A solution of the crude amine in CH2Cl2 (5 mL)
and powdered K2CO3 (342 mg, 2.48 mmol, 8 equiv.) was added followed by benzyl chloroformate
(68.5mg, 0.40 mmol, 1.3 equiv.). Stirring was continued at room temperature for 4 h before addition
of silica (ca. 2 g) and solvent removal under reduced pressure. Purification by flash column
chromatography gave 15 (80 mg, 66 %) with data as reported.4a Under N2, 15 (80 mg, 0.20 mmol, 1
equiv.) in dry THF (5 mL) was treated with LiAlH4 (15.5 mg, 0.42 mmol, 2.1 equiv.). The reaction mixture
was heated to reflux for 2 h. On cooling EtOAc (30 mL) was gradually added followed by 1 M NaOH
solution (30 mL). The resultant aqueous layer was extracted with EtOAc (2 x 30 mL) and the combined
organic extracts were dried over MgSO4. Following filtration and solvent removal flash column
chromatography (CHCl3-MeOH; 19:1, 1 % Et3N) afforded 16 (45 mg, 81 %) as a colorless oil. Rf = 0.1
(CHCl3-MeOH; 19:1, 1 % Et3N). Data corresponds to that previously reported.4a
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Supporting Information
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Copies of H- and 13C{1H}-NMR spectra (PDF) are available free of charge on the ACS Publications
website at DOI:
Acknowledgments
We thank the Libyan Government, Department of Cultural Affairs for the provision of a postgraduate
scholarship (AK, ref. IA8-490-45773) and Dr. Kimberly Geoghegan for useful advice.
References
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