Facile α-deprotunation-electrophilic substitution of quinuclidine and DABCO

Article abstract of DOI:10.1039/a905359j

Deprotonation of BF₃ complexes of quinuclidine or DABCO by Schlosser base and subsequent reaction with electrophiles affords α-substituted products in moderate to good yields.

Full text of DOI:10.1039/a905359j

Facile a-deprotonation–electrophilic substitution of quinuclidine and DABCO
Satinder V. Kessar,* Paramjit Singh, Kamal N. Singh and Sandeep K. Singh
Department of Chemistry, Panjab University, Chandigarh-160014, India. E-mail: svkessar@panjabuniv.chd.nic.in
Received (in Cambridge, UK) 2nd July 1999, Accepted 30th July 1999
Deprotonation of BF3 complexes of quinuclidine or DABCO
by Schlosser base and subsequent reaction with electrophiles
affords a-substituted products in moderate to good yields.
A number of drugs and molecules acting as chiral catalysts have
a quinuclidine (1) framework with an appendage at a carbon
atom a to the bridgehead nitrogen.1 We envisaged a direct
access to such compounds from the basic system via a Lewis
acid promoted amine deprotonation procedure,2 even though
removal of a secondary a-proton from a piperidine ring is often
problematic.3 In the event, strong BF3 activation in conjunction
with the use of a superbase (Bu5Li/ButOK) proved to be
effective for deprotonation of 1 (Scheme 1).4,5 Subsequent
reaction with electrophiles proceeded smoothly to afford a
variety of products 4 in moderate to good yields (Table 1).†
Barton’s N-oxide approach is the only other route available for
similar elaboration of the quinuclidine framework.6 Our method
Scheme 2 Reagents and conditions: i–iii as in Scheme 1.
avoids separate N-oxide formation–deoxygenation steps and the
overall yields for the two procedures are comparable.
The Lewis acid activation method was also explored to obtain
a quinuclidine with an a-attached sulfur atom, which with its
various oxidation states can provide novel bidentate ligands. On
reaction of 1 with diphenyl disulfide under standard conditions
the disubstituted compound 5 was obtained as the major product
(52%). However, it could be cleanly reduced to the desired
monosubstituted compound 6 with lithium naphthalenide in
THF.8 Finally, this methodology was extended to a-deprotona-
tion–electrophilic substitution of DABCO (7) (Scheme 2).‡
This readily available diazabicyclooctane has also been used
extensively to modify organic reactions.9 However, few reports
of the synthesis and use of DABCO analogs of natural and
synthetic quinuclidine compounds have appeared in the lit-
erature and their potential, as ligands and drugs, has remained
largely unexplored.10
Notes and references
† All compounds were characterised by 1H NMR and 13C NMR
spectroscopy and mass spectrometry. Mps of known compounds corre-
sponded with literature values. Selected data for 4f (threo): mp 104–105 °C
(hexane); dH(CDCl3, 300 MHz) 1.13–1.33 (m, 2H), 1.38–1.55 (m, 4H) (C-
3H, C-5H, C-7H), 1.75 (br s, 1H, C-4H), 2.73–2.89 (m, 2H), 2.93–2.99 (m,
2H), 3.05–3.15 (m, 1H) (C-2H, C-6H, C-8H), 4.52–4.55 (d, J 9.7, 1H, C-
9H), 7.43–7.49 (m, 2H, ArH), 7.54–7.57 (d, J 8.6, 1H, ArH), 7.81–7.84 (m,
4H, ArH); dC(CDCl3) 21.5 (CH), 25.8 (CH2), 26.8 (CH2), 29.4 (CH2), 41.4
(CH2), 49.6 (CH2), 62.6 (CH), 74.7 (CH), 125.0 (CH), 125.7 (CH), 125.9
(CH), 126.5 (CH), 127.7 (CH), 127.9 (CH), 128.0 (CH and Cq), 133.2 (Cq),
138.7 (Cq); m/z 268 (M+ + 1, 11.9%), 267 (M+, 54.7), 250 (11.2), 158
(12.0), 141 (14.4), 129 (28.9), 111 (57.2), 82 (100) (Calc. for C18H21NO,
267.1623. Found 267.1628). For 6: mp 65–66 °C (hexane); dH(CDCl3, 300
MHz) 1.25 (br s, 1H), 1.31–1.38 (m, 1H), 1.51–1.54 (m, 3H), 1.82 (br s,
1H), 2.02–2.10 (m, 1H) (C-3H, C-4H, C-5H, C-7H), 2.69–2.78 (m, 1H),
2.99–3.11 (m, 2H), 3.49–3.59 (m, 1H) (C-6H, C-8H), 4.50–4.56 (t, J 8.6,
1H, C-2H), 7.14–7.17 (d, J 7.1, 1H, ArH), 7.22–7.27 (t, J 7 Hz, 2H, ArH),
7.41–7.44 (d, J 7.4, 2H, ArH); dC(CDCl3) 22.7 (CH), 25.5 (CH2), 26.8
(CH2), 34.5 (CH2), 40.8 (CH2), 48.6 (CH2), 65.8 (CH), 126.0 (CH), 128.7
(2CH), 129.2 (2CH), 136.9 (Cq); m/z 220 (M+ + 1, 14.8%), 219 (M+, 100),
218 (17.9), 186 (30.7), 142 (31.5), 110 (80.0), 98 (79.0), 82 (25.8) (Calc. for
Scheme 1 Reagents and conditions: i, BF3.Et2O (1.1 equiv.), 0 °C, 0.25 h,
THF; ii, BusLi/ButOK (2.2 equiv.). 278 °C, 2 h; iii, electrophile (2.2
equiv.), 278 °C, 30 min, 30 min, 230 °C, then HCl (10%); iv, lithium
naphthalenide, THF, 278 °C AcOH.
Table 1 Reaction of deprotonated BF3-complexed bridgehead amines
Yield
Entry Amine Electrophile
Product
(%)a
1
2
3
4
1
1
1
1
BnBr
BzOEt
4a E = Bn
4b E = Bz
34
74
(p-MeOC6H4)2CNO 4c E = C(OH)(p-MeOC6H4)2 68
PhCHNO
4d E = CH(OH)Ph
threob
erythro
72
< 6c
5
6
7
1
1
1
1-Naphthaldehyde 4e E = CH(OH)-1-naphthyl
threo
erythro
41
15
C
13H17NS, 219.1081. Found 219.1083).
2-Naphthaldehyde 4f E = CH(OH)-2-naphthyl
‡ Conditions for a-deprotonation–electrophile reaction of DABCO: To a
solution of ButOK (2.2 mmol) and BusLi (2.2 mmol) in THF (6 ml) at 278
°C was added slowly via a cannula a solution of DABCO–BF3 complex (1.0
mmol) in THF (4 ml) under a nitrogen atmosphere. After stirring for 2 h, a
solution of the electrophile (2.2 mmol) in THF (2 ml) was added dropwise.
The temperature was maintained at 278 °C for 30 min and then allowed to
rise to 230 °C over a period of 30 min. The reaction mixture was quenched
with 10% HCl (5 ml) and worked up.
threo
erythro
40
24
52
4
PhSSPh
5
6
8
9
10
7
7
7
BzOEt
Ph2CNO
8a E = Bz
8b E = C(OH)Ph2
51
72
1-Naphthaldehyde 8c E = CH(OH)-1-naphthyl
threo
erythro
36
40
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a Yields are for pure products isolated after chromatography or crystallisa-
tion. b Ref. 7. c Could not be obtained in pure form.
Chem. Commun., 1999, 1927–1928
This journal is © The Royal Society of Chemistry 1999
1927

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Communication 9/05359J
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Chem. Commun., 1999, 1927–1928