Dearomatisation of 1- and 2-cyanonaphthalene through nucleophilic conjugate addition

Article abstract of DOI:10.1016/S0040-4039(02)00316-7

Conjugate nucleophilic addition of organolithium compounds to 1- and 2-cyanonaphthalene is described for the first time. The dearomatisation is carried out in the presence of HMPA and leads to functionalised dihydronaphthalenes. The nucleophiles used incl

Full text of DOI:10.1016/S0040-4039(02)00316-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2565–2568
Dearomatisation of 1- and 2-cyanonaphthalene through
nucleophilic conjugate addition
Carmen M. Andu´jar Sa´nchez, Ma6 Jose´ Iglesias and Fernando Lo´pez Ortiz*
´
Area de Qu´ımica Orga´nica, Universidad de Almer´ıa, Carretera de Sacramento, 04120 Almer´ıa, Spain
Received 4 February 2002; accepted 14 February 2002
Abstract—Conjugate nucleophilic addition of organolithium compounds to 1- and 2-cyanonaphthalene is described for the first
time. The dearomatisation is carried out in the presence of HMPA and leads to functionalised dihydronaphthalenes. The
nucleophiles used include simple lithium reagents as well as phosphorus-stabilised anions. © 2002 Elsevier Science Ltd. All rights
reserved.
Dearomatisation reactions of naphthalenes bearing
electron-withdrawing groups through conjugate addi-
tion of organometallic reagents have a considerable
potential for the preparation of substances of biological
importance.1 In these processes stable and widely avail-
able materials are transformed into functionalised dihy-
dronaphthalenes with excellent regio- and stereo-
control. Generally, the Michael acceptors used for
the activation of the naphthalene ring are based on
carbonyl2 bearing functional groups or on carbonyl3 or
carboxylic acid derivatives4 and can also be carried out
intramolecularly.5 Oxazolines are among the activating
groups of naphthalenes most extensively applied in
tandem organolithium-electrophile addition pro-
cesses.1a–b,6 Although nitriles are precursors of the 1,3-
oxazoline moiety,7 they have never been directly used as
Michael acceptors in dearomatisation reactions. The
only report on the dearomatisation of a naphthonitrile
corresponds to the reaction of 1-cyanonaphthalene 1
with the carbanion of chloromethyl p-tolyl sulfone 2
leading to a bis-annulated product 3, whose formation
has been explained via tandem addition of the carban-
ion to naphthalene followed by intramolecular nucleo-
philic substitution (Scheme 1).8
the first examples of the conjugate addition of organo-
lithium compounds to naphthonitriles. The use of
HMPA as cosolvent was crucial for achieving the
chemoselective addition of the nucleophile to the aro-
matic ring. The treatment of 1-cyanonaphthalene 1 with
either LiBun, 4b, or LiBus, 4c, at −90°C for 3 h in THF
using HMPA as cosolvent, followed by aqueous work-
up afforded mixtures of the ketone 5 and the dihy-
Ts
CN
CN
NC
+
CHClTs
1
2
Ts
Ts
3
Scheme 1.
R1 = Me, Bun, Bus
O
R1
NC
E
E
5
a
b
c
R1
5
CN
(iv)
(i), (ii) or (iii)
R1Li
6
+
5
CN
R1
4
NC
This exception apart, organolithium reagents com-
monly react with aromatic nitriles through [1,2] addi-
tion to the cyano group, which represents a well-known
method for the synthesis of ketones.9 Here we describe
1
4a: Me
4b: Bun
4c: Bus
4d: CH2PPh2.BH3
R1
7
8
4e: CH3CHPPh2.BH3
E = H, Me, Bn
Keywords: cyanonaphthalene; dearomatisation; dihydronaphthalenes;
conjugate addition; phosphine borane anions.
* Corresponding author. Tel.: +34 950 015478; fax: +34 950 015481;
e-mail: flortiz@ual.es
Scheme 2. Reagents and conditions: (i) −90°C, THF, HMPA
(6 equiv.), 0.5 h; (ii) E‘X’=1N HCl; (iii) EX=MeI or BnBr
(1.2 equiv.), −90°C, 0.5 h; (iv) −90°C, THF, 0.5 h, then H2O.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00316-7

2566
C. M. Andu´jar Sa´nchez et al. / Tetrahedron Letters 43 (2002) 2565–2568
dronaphthalenes 6 and 7 corresponding to the [1,2],
[1,4] and [1,6] adducts of the organolithium to the
nitrile, respectively (Scheme 2). The ratio of regioiso-
mers 6:7 was similar (:5:1) for both RLi reagents,
whereas the yield of dearomatised species increased
from 55% for LiBun to 94% when LiBus was used as
nucleophile (Table 1). On the contrary, under the same
reaction conditions, MeLi 4a gave exclusively the [1,2]
addition product 5a. Apparently, the increase in the
nucleophilic strength of the organolithium species
favored the conjugate addition to the naphthalene sys-
tem. For a given RLi reagent the reactivity is further
enhanced by the deaggregation power of HMPA.10 In
the absence of HMPA [1,2] addition was exclusively
observed in all instances.
the presence of HMPA. Quenching the reactions with
water afforded dihydronaphthalene regioisomers 6d–e/
7d–e in high yield, without traces of the ketones derived
from the [1,2] addition being detected (Table 1). Inter-
estingly, [1,4] addition predominated for lithium phos-
phine borane 4d, while the [1,6] regioisomer was formed
preferentially in the reaction with the secondary carb-
anion 4e. This change in the regioselectivity of the
process can be ascribed to steric interactions produced
by the bulky PPh2·BH3 moiety. Column chromatogra-
phy (mixtures of ethyl acetate:hexane) allowed us to
isolate the compounds in pure form. They were charac-
terized based on their spectroscopic data.11
The intermediate lithiated species formed in the
dearomatization step were also alkylated with methyl
iodide and benzyl bromide in a one-pot reaction lead-
ing to 1,1,2- and 1,1,4-trisubstituted dihydronaphthale-
nes 6f–i and 8f–i,11,14 respectively (Scheme 2).15 For the
[1,6] adducts, alkylation next to the nucleophile was not
observed. Significantly, the successive addition of LiBun
and MeI to 1 led to 74% of dearomatisation, i.e. an
increase of 19% with respect to the use of water as
quenching reagent. This result suggests that the adduct
of attack to the cyano group is in equilibrium with
those of attack to the naphthalene ring and that the
lithium dihydronaphthalenes are alkylated faster thus
displacing the equilibrium in favor of the dearomatised
compounds. On the other hand, the alkylation of the
lithiated species produced by the conjugate addition of
the phosphorus-stabilized anions 4d–e to 1 gave rise to
[1,4] and [1,6] regioisomers in similar ratios to those
obtained when the reaction was quenched with water
(c.f. entries 4–5 and 8–9 in Table 1).
Column chromatography (ethyl acetate:hexane, 1:5)
allowed us to isolate ketones 5, the structural assign-
ment of which was trivial. Compounds 6–7 could not
be separated and were identified through the analysis of
the NMR spectra of the mixtures.11 The signals for the
dearomatised ring appeared in two well defined regions
of the 1H NMR spectra: 2.3–4.3 and 5.8–6.9 ppm,
corresponding to the aliphatic and olefinic protons of
the ring, respectively. The [1,6] adducts showed only
one olefinic proton deshielded due to the conjugation
with the cyano group. On the other hand, compounds 6
were obtained as cis–trans mixtures, with the cis isomer
being formed predominantly.
To increase the scope of the new dearomatisation reac-
tion we studied the viability of introducing function-
alised nucleophiles. Due to our interest in
organophosphorus chemistry,12 we focused on lithium
alkyl(diphenyl)phosphine borane complexes 4d–e.13
These anions added smoothly to 1-cyanonaphthalene in
The analogous conjugate addition reactions of conven-
tional organolithium reagents with 2-cyanonaphthalene
9 proved to be less efficient than with 1: LiBun gave
exclusively the ketone 10a (i.e. [1,2] addition), while
LiBus afforded a mixture of [1,2] and [1,4] addition
products 10 and 11, respectively, either using water or
MeI as quenching electrophile (Scheme 3, Table 2).
These compounds were isolated by column chromato-
graphy (ethyl acetate:hexane, 1:7) and identified
through their spectral data.
Table 1. Distribution of compounds obtained in the reac-
tion of lithium compounds 4 with 1-cyanonaphthalene 1
Comp.
R1
E
Yield (%)
5
6
7
8
a
b
c
d
e
f
g
h
i
Me
100
45
6
Bun
H
H
H
H
Me
Me
Me
Bn
46
78
61
18
52
61
60
19
9
Bus
16
26
62
CH2PPh2·BH3
CH3CHPPh2·BH3
Bun
As expected, 4d–e added regiospecifically to the a posi-
tion of the naphthalene ring of nitrile 9 yielding 1,2-
and 1,4-dihydronaphthalenes 11–12, with 11 being
formed predominantly when the anions were trapped
with methyl iodide and benzyl bromide (Table 2).
23
12
22
26
23
67
Bus
CH2PPh2·BH3
CH3CHPPh2·BH3
R1
R1
O
E
CN
CN
(i)
R1
CN
(ii) or (iii)
E
11
12
9
10
E = H, Me, Bn
Scheme 3. Reagents and conditions: (i) 4, −90°C, THF, HMPA (6 equiv.), 0.5 h; (ii) EX=H2O; (iii) EX=MeI or BnBr (1.2 equiv.),
−90°C, 0.5 h.

C. M. Andu´jar Sa´nchez et al. / Tetrahedron Letters 43 (2002) 2565–2568
2567
Table 2. Yield of compounds obtained in the reaction of
lithium compounds 4 with 2-cyanonaphthalene 9
Sone, T.; Murase, M.; Yamamoto, H. J. Am. Chem. Soc.
2000, 122, 10216.
5. (a) Ahmed, A.; Clayden, J.; Rowley, M. Chem. Commun.
1998, 297; (b) Ahmed, A.; Clayden, J.; Rowley, M.
Tetrahedron Lett. 1998, 39, 6103; (c) Bragg, R. A.;
Clayden, J. Tetrahedron Lett. 1999, 40, 8327; (d) Ahmed,
A.; Clayden, J.; Rowley, M. Synlett 1999, 1954; (e)
Clayden, J.; Menet, C. J.; Mansfield, D. J. Org. Lett.
2000, 2, 4229.
6. For reviews, see: (a) Gant, T. G.; Meyers, A. I. Tetra-
hedron 1994, 50, 2297; (b) Meyers, A. I. J. Heterocyclic
Chem. 1998, 35, 991. See also (c) Kolotuchin, S. V.;
Meyers, A. I. J. Org. Chem. 2000, 65, 3018.
Comp.
R1
E
Yield (%)
10
11
12
a
b
c
d
e
f
Bun
100
45
Bus
H
H
H
Me
Me
Me
Bn
55
45
97
CH2PPh2·BH3
CH3CHPPh2·BH3
Bus
CH2PPh2·BH3
CH3CHPPh2·BH3
CH2PPh2·BH3
39
42
40
73
70
55
g
h
12
19
7. Meyers, A. I.; Oppenlaender, T. J. Am. Chem. Soc. 1986,
108, 1989.
8. Makosza, M.; Glinka, T.; Ostrowski, S.; Rykowski, A.
In summary, conjugate addition of organolithium
reagents to 1- and 2-naphthonitrile has been achieved
for the first time. The use of HMPA as cosolvent is
pivotal for the success of the reaction, which can be
carried out with common organolithium compounds as
well as lithium phosphine borane complexes. The
dearomatised lithium adducts may be protonated with
water or alkylated with MeI and BnBr yielding func-
tionalised dihydronaphthalenes. These are useful com-
pounds due to their applications in organic synthesis.
The phosphine borane derivatives are particularly inter-
esting because this functional group may be used to
perform additional transformations on the a alkyl
chain.
Chem. Lett. 1987, 61.
9. Wibaut, J. P.; Heeringa, L. G. Recl. Trav. Chim. Pays-
Bas 1955, 74, 1003.
10. Reich, H. J.; Barst, J. P.; Dykstra, R. R.; Green, D. P. J.
Am. Chem. Soc. 1993, 115, 8728.
11. The spectra measured included: 1H, 13C, DEPT,
gHMQC, gHMBC, gNOESY, gCOSY. The stereoiso-
mers were readily identified based on the analysis of the
vicinal coupling constants and the correlations observed
in the gNOESY spectra.
12. Ruiz-Go´mez, G.; Lo´pez-Ortiz, F. Synlett, in press.
13. Prepared by metalation of the corresponding
alkyl(diphenyl)phosphine borane with BusLi in THF at
−90°C. The use of HMPA allowed us to reduce the
metalation step from 2 h to 30 min. See: Imamoto, T.;
Kusumoto, T.; Suzuki, N.; Sato, K. J. Am. Chem. Soc.
1985, 107, 5303.
Acknowledgements
14. The [1,6] addition was established from the correlations
observed in the HMBC spectra of 8 for the carbon atom
of the cyano group with the adjacent methyl (8f–h) or
methylene protons (8i) and with one olefinic proton of
the isolated carbonꢀcarbon double bond.
Financial support by the Ministerio de Educacio´n y
Cultura (Project PB97-0587-C02-01) is gratefully
acknowledged. C.M.A.S. thanks the Ministerio de Edu-
cacio´n y Cultura for a doctoral fellowship.
15. Preparation of 6h and 8h. BusLi (1.2 mL of a 1.3 M
solution in cyclohexane, 1.56×10−3 mol) was added to a
solution of methyldiphenylphosphine borane (6.23×10−4
mol) and HMPA (3.74×10−3 mol) in THF (20 mL) at
−90°C. After 30 min of metalation a solution of 1 (6.23×
10−4 mol) in THF (10 mL) was added at −90°C. The
reaction was stirred for 30 min, then MeI was added
(7.5×10−4 mol) and allowed to react for 30 min. Conven-
tional extractive work-up followed by purification by
column chromatography (AcOEt:hexane, 1:7) afforded
fractions containing 6h and 8h. 6h: White solid. Yield:
60%. Mp (°C): 108–110. IR (KBr), w (cm−1): 2197. 1H
NMR (300.13 MHz, CDCl3), l (ppm): 1.57 (s), 2.39 (dt,
References
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1993, 34, 681; (b) Plunian, B.; Mortier, J.; Vaultier, M.;
Toupet, L. J. Org. Chem. 1996, 61, 5206; (c) Shindo, M.;
Koga, K.; Asano, Y.; Tomioka, K. Tetrahedron 1999, 55,
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2
2JHH 13.8, 3JHH=2JPH 11.5 Hz, 1H), 2.86 (ddd, JHH
13.8, 3JHH 2.7, 2JPH 12.5 Hz, 1H), 2.97 (m, 3JHH 2.7, 3JHH
3
3
3
3
6.1, JHH 11.5, JPH 8.4 Hz, 1H), 5.95 (dd, JHH 6.1, JHH
3
9.5 Hz, 1H), 6.22 (d, JHH 9.5 Hz, 1H), 7.1 (m, 1H), 7.32
(m, 1H), 7.45 (m, 7H), 7.6 (m, 1H), 7.65 (m, 2H), 7.75 (m,
2H). 13C NMR (75.46 MHz, CDCl3), l (ppm): 26.26,
2
3
29.22 (d, 1JPC 36.7 Hz), 38.49 (d, JPC 3 Hz), 43.7 (d, JPC
3
12.6 Hz), 122.33, 126.25, 126.45, 127.37, 127.97 (d, JPC
1.2 Hz), 128.69 (d, JPC 10.2 Hz), 128.85, 128.87, 128.97
(d, JPC 9.6 Hz), 129.17 (d, JPC 57.1 Hz), 129.27 (d, JPC
3
3
1
1
4
4
45 Hz), 130.45, 131.4 (d, JPC 1.2 Hz), 131.43 (d, JPC 1.2
Hz), 132.03 (d, 2JPC 9.6 Hz), 132.1, 132.3 (d, 2JPC 9.6 Hz).

2568
C. M. Andu´jar Sa´nchez et al. / Tetrahedron Letters 43 (2002) 2565–2568
2
31P NMR (121.49 MHz, CDCl3), l (ppm): 14.2. Anal.
calcd for C25H25BNP (381.05): C, 79.01; H, 6.44; N, 3.82.
Found: C, 78.8; H, 6.29; N, 3.67. MS, m/z (%): 404
(M++23).
MHz, CDCl3), l (ppm): 32.23, 34.19 (d, JPC 1.8 Hz),
1
36.91, 36.99 (d, JPC 32.3 Hz), 122.98, 126.56, 127.36,
4
3
127.63, 128.55 (d, JPC 2.2 Hz), 128.56, 128.92 (d, JPC
1
3
10.2 Hz), 128.98 (d, JPC 54.7 Hz), 129 (d, JPC 9.6 Hz),
1
3
1
8h. Oil. Yield: 23%. IR (KBr), w (cm−1): 2197. H NMR
129.33 (d, JPC 56.5 Hz), 130.05 (d, JPC 1.8 Hz), 131.47
(d, JPC 2.9 Hz), 131.65 (d, JPC 2.2 Hz), 132.01 (d, JPC
4
4
2
2
(300.13 MHz, CDCl3), l (ppm): 1.77 (s), 2.48 (dt, JHH
2
3
3
2
3
14.3, JHH=2JPH 10.8 Hz, 1H), 2.7 (ddd, JHH 14.3, JHH
8.8 Hz), 132.33 (d, JPC 8.8 Hz), 134.26, 136.8 (d, JPC
11.4 Hz). 31P NMR (121.49 MHz, CDCl3), l (ppm): 14.3.
Anal. calcd for C25H25BNP (381.05): C, 79.01; H, 6.44;
N, 3.82. Found: C, 78.8; H, 6.29; N, 3.67. MS, m/z (%):
404 (M++23).
2
3
3
3.2, JPH 11.6 Hz, 1H), 3.95 (m, JHH 3.2, JHH 4.9,
3JHH=3JPH 10.8 Hz, 1H), 5.79 (d, JHH 10.5 Hz, 1H),
3
3
3
5.95 (dd, JHH 4.9, JHH 9.8 Hz, 1H), 7.13 (m, 1H), 7.27
(m, 2H), 7.53 (m, 7H), 7.76 (m, 4H). 13C NMR (75.46