Carbolithiation of aromatic rings: Cyclohexadienes from N-aroyl-2,2,6,6-tetramethylpiperidines

Article abstract of DOI:10.1039/b206479k

Benzamides whose nitrogen atom is part of a 2,2,6,6-tetramethylpiperidine ring are dearomatised by alkyllithiums, which attack them regioselectively to yield, after electrophilic quench, substituted cyclohexadienes.

Full text of DOI:10.1039/b206479k

Carbolithiation of aromatic rings: cyclohexadienes from
N-aroyl-2,2,6,6-tetramethylpiperidines
Jonathan Clayden,* Yann J. Y. Foricher and Ho Kam Lam
Department of Chemistry, University of Manchester, Oxford Road, Manchester, UK M13 9PL.
E-mail: j.p.clayden@man.ac.uk
Received (in Cambridge, UK) 4th July 2002, Accepted 29th July 2002
First published as an Advance Article on the web 22nd August 2002
Benzamides whose nitrogen atom is part of a 2,2,6,6-tetra-
methylpiperidine ring are dearomatised by alkyllithiums,
which attack them regioselectively to yield, after electro-
philic quench, substituted cyclohexadienes.
To evaluate the scope of the nucleophilic dearomatisation, we
treated a small range of TMP amides 1 and 5–7‡ with
organolithiums RLi (n-BuLi, s-BuLi, and MeLi), quenching
+
with a range of electrophiles E (Scheme 2). Table 1 shows the
results of this study.
Dearomatisation of aromatic rings allows chemists to super-
impose stereoselective reactions upon the regiochemical control
available with aromatic substitution chemistry, both classical
The enolate produced by addition of s-BuLi to 1 reacted with
a range of electrophiles in moderate to good yield (entries 1–5).
Except for protonation, which gave a mixture of regioisomers,
the extended enolates always reacted at their termini, yielding
the 2,3-disubstituted cyclohexanecarboxamides 3. The electro-
philic quench was stereoselective, giving only the trans
diastereoisomer. n-BuLi and MeLi also added to 1, and
although yields were lower than with s-BuLi, single diastereoi-
somers of products 3f and 3g were obtained in each case (entries
6 and 7). The remainder of the material was largely made up of
unreacted starting amide.
The p-methoxy substituent assists but is not necessary for the
dearomatising addition. N-Benzoyl-2,2,6,6-tetramethylpiper-
idine 7, for example, reacts with s-BuLi to give a comparable
enolate 14 whose quench with methyl iodide yields 15 as a
mixture of diastereoisomers (entry 11).
1
and metallation-directed. Methods for partial dearomatisation
are particularly useful for making substituted cyclohexanes and
cyclohexenes since they can give synthetic intermediates
containing a valuable combination of reactive unsaturated
2–4
functional groups. Other than Birch reduction, which allows
only electrophilic functionalisation of the ring, rapid dearoma-
tising elaboration of benzenoid rings is best achieved by
nucleophilic addition to an electron deficient arene lacking
other points of electrophilic reactivity.5
The need for an electron-withdrawing group which is not
itself electrophilic is the greatest limitation to new inter-
6
molecular dearomatising addition reactions. The most com-
mon solution to this problem is to complex the ring with a metal,
usually chromium, which permits ring addition with stereo- and
7
regiocontrol. An alternative strategy is to employ a carbonyl-
substituted starting material but to block reactivity at the
carbonyl group itself, for example with hindered Lewis acids.8
In this communication, we show that amides of 2,2,6,6-tetra-
methylpiperidine (TMP) perform in a similar role, allowing the
addition of an organolithium and an electrophile across one of
the double bonds of an arene in the manner of a carbolithiation
reaction.9
Treatment of 1 with s-BuLi in THF at 278 or 0 °C and then
methyl iodide in an attempted ortholithiation reaction gave,
instead of the expected10 4, a good yield of the dearomatised
compound 3a as a mixture of diastereoisomers at the stereo-
genic centre in the sec-butyl group (Scheme 1).† Nucleophilic
addition to the aromatic ring takes place in preference to
deprotonation, forming an extended enolate 2 which alkylates at
its terminus.
Scheme 1 TMP amides and sec-butyllithium.
Scheme 2 Carbolithiation of TMP amides.
2
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CHEM. COMMUN., 2002, 2138–2139
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Table 1 Dearomatising carbolithiation–quench of TMP amides
Starting
material
Entry
R
E+
Product
Yield (%)
1
2
3
4
5
6
7
8
9
1
s-Bu
MeI
BnBr
EtI
9a ( = 3a) 71a
a
9b
9c
9d
9e
9f
61
51
32
76
40
22
12
23
15
55
a
a
(CH
2
)
3
CNO
ab
4
NH Cl
Scheme 4 Deprotecting the amide.
n-BuLi
MeLi
s-Bu
MeI
MeI
MeI
MeI
9g
5
6
11a
13a
13b
15a
aromatic rings as precursors of substituted cyclohexane deriva-
tives without recourse to transition metal chemistry.
We are grateful to the EPSRC and to GlaxoSmithKline for
support.
s-Bu
c
1
1
a
0
1
4
NH Cl
7
s-Bu
MeI
b
3
+1 Mixture of diastereoisomers at Et(Me)CH. Mixture of g and e-
c
protonated regioisomers. a-Protonated regioisomer.
Notes and references
†
Typical procedure: sec-Butyllithium (1.3 M in hexane, 0.68 ml, 1.2
equiv.) was slowly added to a stirred solution of the amide 1 (0.20 g, 0.74
mmol) in dry THF (7 ml) at 0 °C under nitrogen. After 1 h, iodomethane
(0.14 ml, 3 equiv.) was added and the mixture was allowed to warm to room
temperature. After a further 45 min, a saturated solution of ammonium
chloride (15 ml) was added and the mixture was extracted with ethyl acetate
(2 3 20 ml). The combined organic phases were washed with brine (2 3 20
ml) and dried over magnesium sulfate. Concentration under reduced
pressure yielded the crude product as yellow oil. Purification by flash
chromatography (1+14 EtOAc–petroleum ether (bp 40–60)) afforded the
dearomatised product 3a (0.19 g, 71%) as a mixture of diastereoisomers
(3+1), plus starting material 1 (12 mg, 6%). Data for major diastereoisomer:
Scheme 3 Conformation and reactivity.
d
2
2
1
H 3
(300 MHz; CDCl ): 7.40 (1 H, d, J 6.6), 4.97 (1 H, d, J 6.6), 3.66 (3H, s),
.69 (1 H, d, J 2.7), 2.28 (1 H, q, J 7.2), 1.72 (3H, m), 1.52 (3 H, td, J 6.0,
.4), 1.28–1.20 (12 H, m), 1.06–0.92 (6 H, m) and 0.72 (3 H, d, J 6.9); nmax
625 cm (CNO); MS: found, M + H , m/z 348.2903. C23H38NO requires
2
Other substituted benzamides react less efficiently. The
,4-dimethoxybenzamide 5 reacts in a manner analogous to 1
3
21
+
and 7 but only very slowly—the reaction in entry 8 returns
mainly starting amide. The m-methoxy substituted compound 6
by contrast undergoes addition of s-BuLi at the para position,
and quenching with MeI or protonation generates diastereo-
isomers of 13a and 13b.
Amides of TMP have unusual structural features, which
display themselves spectroscopically, and which may shed light
on this unusual reactivity.11 Most significantly, the barrier to C–
M, 348.2902.
The amides were formed by heating to reflux the appropriate acyl chloride
with the sodium salt of 2,2,6,6-tetramethylpiperidine in toluene for 24 h.
‡
1
2
3
4
5
T. Bach, Angew. Chem., Int. Ed., 1996, 35, 729.
L. N. Mander, Synlett, 1991, 134.
P. W. Rabideau and Z. Marcinow, Org. React., 1992, 42, 1.
A. G. Schultz, Chem. Commun., 1999, 1263.
Naphthalenes and some heteroaromatics have a greater tendency to
dearomatise by nucleophilic addition. See, for representative examples:
S. V. Kolotuchin and A. I. Meyers, J. Org. Chem., 2000, 65, 3018; K.
Tomioka, M. Shindo and K. Koga, Tetrahedron Lett., 1990, 31, 1739; B.
Plunian, J. Mortier, M. Vaultier and L. Toupet, J. Org. Chem., 1996, 61,
2
1
11
12
N rotation in the amides is particularly low: 28 kJ mol for 7
2
1
compared with ca. 65 kJ mol for N,N-dimethylbenzamide.
This must be due to steric encumbrance of the normal planar
amide structure, and we propose that while 1 probably adopts
conformation 16a, with the ring twisted out of the amide plane,
as its ground state, a de-conjugated conformation approximat-
ing to 16b is relatively easily accessible (Scheme 3). In
conformation 16b, Ar–CO conjugation activates the ring
towards nucleophilic attack while the four methyl groups shield
the carbonyl from the incoming nucleophilic reagent, and we
propose that dearomatisation arises by attack on 16b.
The TMP feature of the amide is relatively sensitive to
cleavage under acid conditions. For example, treatment of 3a ( =
a) with iodotrimethylsilane in the absence of light cleaved both
the enol ether and the TMP ring, yielding the secondary amide
7 in 50% yield (Scheme 4).
5
206; J. Clayden, C. S. Frampton, C. McCarthy and N. Westlund,
Tetrahedron, 1999, 55, 14161; J. Clayden and M. N. Kenworthy, Org.
Lett., 2002, 4, 787; F. Rezgui, P. Mangeney and A. Alexakis,
Tetrahedron Lett., 1999, 40, 6241; D. L. Comins, X. Zheng and R. R.
Goehring, Org. Lett., 2002, 4, 1611.
6
A number of intermolecular dearomatising reactions—dearomatising
cyclisations—and rearrangements have been reported. For recent
examples, see: J. Clayden, C. J. Menet and D. J. Mansfield, Org. Lett.,
2000, 2, 4229 and references therein.
7 E. P. Kündig, D. Amurrio, G. Anderson, D. Beruben, K. Khan, A. Ripa
and L. Ronggang, Pure Appl. Chem., 1997, 69, 543.
9
8
K. Maruoka, M. Ito and H. Yamamoto, J. Am. Chem. Soc., 1995, 117,
091.
9
1
9
S. Norsikian, I. Marek, S. Klein, J. F. Poisson and J. F. Normant, Chem.
Eur. J., 1999, 5, 2055.
Treatment of hindered amides with strong bases is well
established as a method for the synthesis of aromatic com-
pounds by ortholithiation.10 This reaction appears to place some
limits of the types of amides which may be successfully
ortholithiated, but it also opens up new prospects for the use of
1
0 V. Snieckus, Chem. Rev., 1990, 90, 879.
1
1 L. Lunazzi, D. Macciantelli, D. Tassi and A. Dondoni, J. Chem. Soc.,
Perkin Trans. 2, 1980, 717.
12 W. H. Stewart and T. H. Siddall, Chem. Rev., 1970, 70, 517.
CHEM. COMMUN., 2002, 2138–2139
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