Quinuclidine N-oxide: A potential replacement for HMPA

Article abstract of DOI:10.1039/a808779b

The use of quinuclidine N-oxide as a replacement for HMPA is described.

Full text of DOI:10.1039/a808779b

Quinuclidine N-oxide: a potential replacement for HMPA
a
b
a
Ian A. O’Neil,* Justine Y. Q. Lai and Duncan Wynn
a
Robert Robinson Laboratories, Department of Chemistry, University of Liverpool, Crown St, Liverpool, UK
L69 7ZD. E-mail: ion@liv.ac.uk
Rhone Poulenc Rorer, Rainham Rd South, Dagenham, Essex, UK RM10 7XS
b
Received (in Cambridge, UK) 10th November 1998, Accepted 17th November 1998
O
O
The use of quinuclidine N-oxide as a replacement for HMPA
(i) LDA (2 equiv.), THF, –78 °C
is described.
O2N
OMe
O2N
OMe
(ii) BnBr
Bn
There are numerous significant and important reactions in
organic synthesis which require the addition of hexamethyl-
2
3
1
Additive (equiv.)
Yield (%)
phosphoric triamide (HMPA) to render them viable. HMPA is
a dipolar aprotic compound with a superb ability to form cation–
ligand complexes and it can enhance the rates of a wide variety
of main group organometallic reactions. In addition, it can also
influence the regio- and stereo-chemistry of key reactions such
as enolate formation. Other reactions in which HMPA can
enhance reactivity include carbanion formation, carbanion
reactivity, carbanion regioselectivity (1,2 vs. 1,4 addition), ylide
reactivity and anion reactivity. In essence, it is thought that
0
8
HMPA (5.2)
DMPU (10)
QNO (1.4)
QNO (3.0)
QNO (5.0)
85
85
37
47
78
Scheme 2
HMPA acts as a metal binding agent, disrupting the aggregation
Our investigations started with the alkylation of the dianion
of methyl 3-nitropropionate, a reaction that is known to require
5 equiv. of HMPA to proceed in good yield. It was found that
with just 3 equiv. of QNO the required product was isolated in
a reasonable 47%, and the use of 5 equiv. gave a yield
comparable to that with HMPA (Scheme 2).
We next examined the regioselectivity of addition of
2-lithiodithiane to cyclohex-2-en-1-one. In the absence of
HMPA the predominant mode of addition is 1,2. When 1 equiv.
of HMPA is added the 1,4 addition product becomes the major
states that enolates normally exist in.2
HMPA is a listed mutagen and as such does not find
widespread use either in industry or academia. Several other
substances, such as 1,3-dimethyl-3,4,5,6-tetrahydropyrimidin-
2
(1H)-one (DMPU) have been used as replacements but all
3
have their limitations. An amine oxide bears the same type of
charge distribution as a phosphine oxide, but the dipole moment
is much larger. Therefore an amine oxide would be expected to
behave in a similar fashion to a reagent such as HMPA. The
major problem lies with the instability of most amine oxides
towards strong bases, azomethine ylide formation being the
8
one. Addition of QNO switched the reaction to give the 1,4
addition product with good selectivity (Scheme 3). Indeed, it
was considerably more selective than the use of DMPU.
4
most common pathway.
As a consequence of our previous work with amine oxides,5
we have carried out preliminary studies using quinuclidine N-
oxide (QNO) as a replacement for HMPA, since it is an amine
oxide that is known to be stable in strongly basic conditions.
S
n
S
S
S
(i) Bu Li, THF, –78 °C
S
+
(ii) Additive
S
t
(iii) Cyclohex-2-en-1-one
O
Indeed, it can be deprotonated with Bu Li and the corresponding
anion can be reacted with aldehydes and ketones. This amine
OH
6
4
5
6
oxide is stable because elimination of lithium oxide would lead
to a bridgehead iminium ion (anti-Bredt) (Scheme 1).
We chose to study four key reactions in which HMPA is
known to play a vital role and we have investigated the effect of
replacing the HMPA by quinuclidine N-oxide. The reactions
examined were enolate alkylation,7 1,4 vs. 1,2 addition,8
Additive (equiv.)
Yield (%)
Yield (%)
—
8
88
95
82
88
90
92
12
5
18
12
10
HMPA (1)
HMPA (2)
DMPU (2)
QNO (1)
QNO (2)
9
10
diastereoselective nitroaldol reactions and epoxide opening.
Quinuclidine N-oxide has been prepared by the oxidation of
quinuclidine with 30% H
in MeOH.11 However, we
2 2
O
routinely use MCPBA as the oxidant as it is more convenient on
a laboratory scale.12 The product can be purified by chromatog-
raphy on silica gel. The product is dried under vacuum over
Scheme 3
We then studied the addition of the dianion of 1-nitropropane
to benzaldehyde. This gives the nitroaldol products as a mixture
of diastereoisomers. In the presence of HMPA, the syn
diastereoisomer is the major product. The addition of 1.5
equiv. of QNO was also found to promote formation of the syn
P
2
O
5
. It is a hygroscopic solid and needs to be stored under
vacuum over P . The quinuclidine nucleus is ideal since it is
2 5
O
a rigid structure amenable to rapid modification. In addition, a
number of functionalised derivatives can be readily made, some
in chiral form.13
9
diastereoisomer giving a 4:1 mixture of diastereoisomers in
6
2%. The addition of more QNO did not appear to improve the
selectivity (Scheme 4).
Finally, Denmark and co-workers have recently reported the
t
(
i) Bu Li
R
(
(
ii) RCHO
iii) H3O
4
use of HMPA and SiCl to cleave epoxides to give chlorohy-
N
N
N
+
10
drins. With a chiral phosphinamide, the ring opening of meso
epoxides gave enantiomerically enriched chlorohydrins. It was
gratifying to find that QNO mediated the ring opening of
cyclohexene oxide to give the chlorohydrin in a yield identical
O–
O–
OH
1
Scheme 1
Chem. Commun., 1999, 59–60
59

OH
OH
n
Notes and references
1 R. R. Dykstra, Encyclopedia of Organic Reagents, ed. L. Paquette,
Bu Li (2 equiv.), THF, –78 °C
NO2
+
Ph
Ph
PhCHO (1 equiv.)
HOAc (2.5 equiv.)
Additive
1
995, vol. 4, p. 2668.
NO2
NO2
2
3
4
D. Seebach, Angew. Chem., Int Ed. Engl., 1988, 27, 1624.
7
8
9
T. Mukhopadhyay and D. Seebach, Helv. Chim. Acta., 1982, 65, 385.
R. Beugelmans, L. Benadjila-Iguertsira and G. Roussi, J. Chem. Soc.,
Chem. Commun., 1982, 544; G. Roussi and J. Zhang, Tetrahedron,
Aditive (equiv.)
Yield (%)
Yield (%)
1
991, 47, 5161.
HMPA (5)
QNO (1.5)
QNO (3)
90
81
79
10
19
21
5 I. A. O’Neil, N. D. Miller, J. Peake, J. V. Barkley, C. M. R. Low and S.
B. Kalindjian, Synlett, 1993, 515; I. A. O’Neil, N. D. Miller, J. V.
Barkley, C. M. R. Low and S. B. Kalindjian, Synlett, 1995, 617 and 619;
I. A. O’Neil, C. D. Turner and S. B. Kalindjian, Synlett, 1997, 777; I. A.
O’Neil and A. J. Potter, Tetrahedron Lett., 1997, 38, 5731; I. A. O’Neil
and A. J. Potter, Chem. Commun., 1998, 1487.
Scheme 4
OH
Cl
SiCl4, CH2Cl2, –78 °C
Additive
6 D. H. R. Barton, R. Beuglmans and R. N. Young, Nouv. J. Chim., 1978,
2, 363.
O
7
8
9
D. Seebach, R. Henning and T. Mukhopadhyay, Chem. Ber., 1982, 115,
705.
C. A. Brown and A. Yamaichi, J. Chem. Soc., Chem. Commun., 1979,
101.
1
10
11
Additive (equiv.)
Yield (%)
F. Lehr, J. Gonnermann and D. Seebach, Helv. Chim. Acta., 1979, 62,
HMPA (0.1)
QNO (0.1)
89
89
2
259.
1
0 S. E. Denmark, P. A Barsanti, K. T. Wong and R. A. Stavenger, J. Org.
Chem., 1998, 63, 2428; S. E. Denmark, D. M. Coe, N. E. Pratt and B. D.
Griedel, J. Org. Chem., 1994, 59, 6161.
Scheme 5
1
1 S. Srinivas and K. G. Taylor, J. Org. Chem., 1990, 55, 1779; H. C. Kolb,
P. G. Andersson and K. B. Sharpless, J. Am. Chem. Soc., 1994, 116,
1278.
to that obtained using HMPA. In the absence of QNO the
chlorohydrin was isolated in low yield (Scheme 5).
Significantly, QNO was found to be negative in the bacterial
reverse mutation test conducted on Salmonella typhimurium
TA98, TA100 and TA102 in the presence or absence of
metabolic activation. Additionally it was also found to be
negative in the test to evaluate its potential to induce
micronuclei in Chinese hamster ovary cells using the cytokine-
sis block method in the presence or absence of metabolic
activation.
12 J. C. Craig and K. K. Purushothaman, J. Org. Chem., 1970, 35, 1721.
1
3 K. A. Bairamov, A. G. Douglass and P. Kaszynski, Syn. Commun.,
1
1
998, 28, 527; M. Langlois, C. Meyer and J. L. Soulier, Syn. Commun.,
992, 22, 1895.
1
4 Alkylation of methyl 3-nitropropanoate: A solution of diisopropylamine
0.9 ml, 0.63 mmol) and quinuclidine N-oxide (1.78 g, 14 mmol) in dry
THF (40 ml) was cooled to 278 °C. To this solution was added BuLi
4.0 ml, 1.6 m in hexane, 0.63 mmol). The solution was stirred for 30
(
(
min, then methyl 3-nitropropanoate (0.37 g, 2.8 mmol) was added. After
stirring for 60 min benzyl bromide (0.4 ml, 0.35 mmol) was added. The
solution was stirred for 5 h. Acetic acid (1.0 ml, 2.8 mmol) was added
followed by distilled water (5.0 ml). The solution was warmed to room
temperature and water (50 ml) was added. Diethyl ether (50 ml) was
added, the organic layer separated and the aqueous layer extracted with
diethyl ether (3 3 50 ml). The combined organic layers were washed
In summary, we have shown that quinuclidine N-oxide can
act as a replacement for HMPA in a range of reactions.14 We are
currently exploring other reactions known to require HMPA,
and synthesising second generation quinuclidine N-oxides
which are chiral and bear additional metal binding sites for
enhanced reactivity and solubility. Their properties, applica-
tions and use in a range of asymmetric transformations will be
reported shortly.
We would like to thank the EPSRC for a studentship (to
D. W.). I. O. N. would like to thank the James Black Foundation
for their continued financial support and Cambridge Combina-
torial for a generous unrestricted research grant.
4
with water (100 ml), and dried over MgSO . The solvent was removed
in vacuo. The crude reaction mixture was purified by flash chromato-
graphy over silica gel eluting with EtOAC–light petroleum (bp
40–60 °C), 1 : 9 to give the desired product (0.48 g, 78%). The aqueous
layer contains the quinuclidine N-oxide.
Communication 8/08779B
60
Chem. Commun., 1999, 59–60