Atroposelective attack of nucleophiles on 2-formyl-1-naphthamides and their derivatives: Chelation and non-chelation control

Article abstract of DOI:10.1039/b000669f

Organometallic nucleophiles attack 2-formyl-1-naphthamides to give secondary alcohols with widely varying atroposelectivity. By careful choice of reagent, selectivities of up to >99:1 in favour of either the anti or the syn atropisomer can be obtained. Ethers and amines may be synthesised atroposelectively from acetals or imines. The sense of the selectivity is determined by the reactive conformation of the Ar-CHO bond, itself dependent on the coordinating and chelating ability of the nucleophile's counterion. The roles of conformation, Lewis acids, and chelation/non-chelation control in relation to stereoselectivity are discussed.

Full text of DOI:10.1039/b000669f

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Atroposelective attack of nucleophiles on 2-formyl-1-naphthamides
and their derivatives: chelation and non-chelation control
Jonathan Clayden,*a Catherine McCarthy,a Neil Westlunda and Christopher S. Framptonb
1
a Department of Chemistry, University of Manchester, Oxford Rd., Manchester, UK M13 9PL
b Roche Discovery Welwyn, 40 Broadwater Rd., Welwyn Garden City, Herts, UK AL7 3AY
Received (in Cambridge, UK) 24th January 2000, Accepted 10th March 2000
Organometallic nucleophiles attack 2-formyl-1-naphthamides to give secondary alcohols with widely varying
atroposelectivity. By careful choice of reagent, selectivities of up to >99:1 in favour of either the anti or the syn
atropisomer can be obtained. Ethers and amines may be synthesised atroposelectively from acetals or imines. The
sense of the selectivity is determined by the reactive conformation of the Ar–CHO bond, itself dependent on the
coordinating and chelating ability of the nucleophile’s counterion. The roles of conformation, Lewis acids, and
chelation/non-chelation control in relation to stereoselectivity are discussed.
sensitive to the nature of the organometallic used and to the
Introduction
conditions of the reaction.18 Examples of additions to chiral
aldehydes with high levels of (1,3)-,15,19,20 and more remote21,22
asymmetric induction have also been reported. There are a few
reports of the use of planar23,24 or axial25 chirality to govern the
direction of attack on aldehydes.
In the previous paper1 we described the synthesis of secon-
dary alcohols 1 by atroposelective reduction of the corre-
sponding ketones 2 (Scheme 1, disconnection (a)). We had
earlier reported the synthesis of the same class of alcohols by
atroposelective addition of ortholithiated 1-naphthamides 3 to
aldehydes (disconnection (b)).2,3 In this paper we turn to the
third possible route to the alcohols, indicated by disconnection
(c)—the addition of an alkyl metal reagent to a 2-formyl-
naphthamide 4.4 We also consider the atroposelective addition
of nucleophiles to the oxonium and imine5 derivatives of 4
(leading to ethers 21 and amines 24–27).
Results and discussion
Synthesis of 2-formyl-1-naphthamides
The aldehydes 4 were very conveniently made from their parent
1-naphthamides 3 by ortholithiation26 and reaction with DMF
(Scheme 2, Table 1). The yield of 4b and 4e was lowered by a
competing addition of s-BuLi to the aromatic ring. The syn-
thesis of 4b, for example, also produced four diastereoisomers
of the amides 5 in 65% yield. Addition to the ring appears to be
a problem when one of the N-alkyl groups is particularly large,
and may be a result of hindrance to O–Li coordination.27
Only 4a could not be made in this way: N,N-dimethylamides
are generally too electrophilic (at the carbonyl group) to
undergo ortholithiation.26 Instead, we made 4a from 1-bromo-
2-methylnaphthalene 6 (Scheme 3). Bromination29 and Hass–
Bender oxidation30 gave the aldehyde 829,31 which was protected
as its dioxolane 9.32 Bromine–lithium exchange gave an organo-
lithium which reacted with N,N-dimethylcarbamoyl chloride
to yield naphthamide 10 which was deprotected using acid to
give 4a.
Conformational freedom around the R–CHO bond means
that nucleophilic attack on chiral aldehydes6 only rarely
exhibits high levels of stereoselectivity. Additions of Grignard
reagents to simple acyclic chiral aldehydes typically give up to
80:20 selectivity.7,8 More complex aldehydes containing bulky
N,N-dibenzylamino groups9,10 or silyl substituents11 or lacking
free rotation12 demonstrate rather higher levels of selectivity.
Cram and Wilson13 noted that metal chelation by the aldehyde
carbonyl oxygen and a second heteroatom may increase the
stereoselectivity considerably, and in favourable cases, simple
chiral aldehydes bearing alkoxy substituents may react with
>90:10 stereoselectivity with Grignard reagents and, to a lesser
extent, organolithiums.14,15 Higher selectivities still may be
obtained, for example, by the use of RTiCl3 reagents,16,17 but in
general selectivity in chelation-controlled addition is supremely
Scheme 1 Atroposelective routes to 1.
DOI: 10.1039/b000669f
J. Chem. Soc., Perkin Trans. 1, 2000, 1363–1378
This journal is © The Royal Society of Chemistry 2000
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Additions of nucleophiles to 2-formyl-1-naphthamides 4
Phenyl and butyl additions are more selective than allyl addi-
tions, with the methyl additions lying in between. Selectivity
also varies with the N-substituents R1 and R2: generally,
but by no means always, the Ni-Pr2 aldehyde 4d reacts with
slightly higher selectivity than the NEt2 aldehyde 4c. The
N(CHPr2)2 aldehyde 4e underwent the most anti-selective (with
MeLi, entry 1) and the most syn-selective (with PhMgBr, entry
17) reactions of all, but its reactions with BuLi (entry 2)
and BuMgBr (entry 13) were notably unselective, and gave
significant amounts of the reduction product 16e. Our first
conclusion, therefore, is that the reactions of 4 are controlled
We started by treating the aldehydes 4 with a range of simple
organolithium and Grignard reagents in THF at Ϫ78 ЊC as
shown in Scheme 4 and Table 2: methyllithium (entry 1), butyl-
lithium (entry 2), octynyllithium (entry 7), phenyllithium
(entry 10); and methylmagnesium bromide (entry 12), butyl-
magnesium chloride (entry 13), phenylmagnesium bromide
(entry 17), allylmagnesium bromide (entry 18). The reactions
gave moderate to excellent yields of the alcohols 11–15 but with
selectivities varying greatly, from 140:1 syn to >99:1 anti.
The additions have one simple overriding feature: all the
Grignard reagents add with syn-selectivity, and (apart from
PhLi and octynyllithium) the organolithiums add with anti-
selectivity. Other than this, the trends are much less distinct.
Scheme 2 Synthesis of aldehydes 4 (i) s-BuLi, THF, Ϫ78 ЊC; (ii)
Me2NCHO, Ϫ78 ЊC.
Table 1 Synthesis of aldehydes 4
Starting
material
Entry
R1
R2
Product
Yield (%)
1
2
3
4
Me
Et
i-Pr
CH(n-Pr)2
t-Bu
Et
i-Pr
CH(n-Pr)2
3b
3c
3d
3e
4b
4c
4d
4e
33a
78
8228
Scheme 3 Synthesis of 4a; (i) NBS, (PhCO2)2, CCl4, (60%); (ii) 2-nitro-
propane, NaOEt, EtOH, (62%); (iii) HOCH2CH2OH, p-TsOH, PhH,
(91%); (iv) 1. t-BuLi × 2, 2. ClCONMe2; (v) p-TsOH, AcMe (83% over
2 steps).
59 or 442
a Plus 5 (65%).
Table 2 Additions of nucleophiles to aldehydes 4
From 4c
From 4d
From 4e
Additives
(equiv.)
Product,
Ratiob
anti:syn
Product,
Ratiob
anti:syn
Product,
Ratiob
anti:syn
Entry
Reagent
yielda (%)
yielda (%)
yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
MeLi
n-BuLi
—
—
11c 94
12c 56
12c 63
12c 67
12c 49
—
—
—
—
14c 52
14c —e
11c 91
12c 72
12c 68
12c 83
12c 74
14c 81
15c 97
11c 70
12c 64
13c 76
14c 97
15c 92
11c 48 ϩ 12h
18h
71:29
85:15
66:34
57:43
43:57
—
—
—
—
19:81
27:73
25:75
14:86
38:62
43:57
37:63
14:86
42:58
98:2
74:26
95:5
11:89
71:29
6:94
—
11d 90
12d 83
12d 65
12d 41
12d 59
12d 56
13d 90
13d 66
13d 50
14d 95
14d —e
11d 66
12d 57
12d 62
12d 61
12d 89
14d 71
15d 94
11d 99
12d 63
13d 52
14d 96
15d 100
11d 41 ϩ 13h
23h
80:20
85:15
73:27
48:52
45:55
94:6
11e 99
>99:1
49:51
—
—
—
—
—
—
—
—
—
—
34:66
—
—
—
1:140
—
>99:1
—
12e 91 ϩ 6c
HMPA (4)
—
—
—
—
—
—
—
—
BF3ؒOEt2 (1)d
BF3ؒOEt2 (2)d
Me3Al (0.1)
—
Me3Al (0.1)
i-Bu2AlH (1)
OctynylLi
PhLi
20:80
93:7
>99:1
34:66
33:67
23:77
15:85
32:68
50:50
32:68
3:97
40:60
300:1
125:1
125:1
85:15
77:28
65:35
—
—
HMPA (4)
—
—
—
—
MeMgBr
n-BuMgCl
12e 33 ϩ 33c,f
HMPA (4)
—
—
—
14e 90
—
11e 59
—
—
—
—
—
—
MgBr2 (1)d
ZnBr2 (1)d
PhMgBr
AllylMgBr
—
—
—
—
—
—
MeTi(Oi-Pr)3
n-BuTi(Oi-Pr)3
OctynylTi(Oi-Pr)3
PhTi(Oi-Pr)3
AllylTi(Oi-Pr)3
MeTiCl3
—
—
—
—
—
g
i
MeTiCl3
—
a Isolated yield of mixture. b Determined by analytical HPLC. c Yield of reduction product 16. d CH2Cl2 in the absence of THF. e Product not
isolated. f n-BuMgBr used. g Reagent formed in situ from MeMgBr ϩ TiCl4. h Yield of pinacol product 17. i Reagent formed in situ from
MeLi ϩ TiCl4.
1364
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(entries 3, 11, 14, Table 2) in an attempt to prevent amide–
aldehyde chelation: in all cases selectivity decreased, becoming
more syn-selective from BuLi and more anti-selective from PhLi
and BuMgCl. We also repeated the reactions of BuLi and
BuMgCl in CH2Cl2 in the presence of Lewis acids: BF3ؒOEt2
(1 or 2 equiv., entries 4 and 5) to discourage chelation and
MgBr2 and ZnBr2 (entries 15, 16) to encourage it. Again, the only
effect was that the selectivity, in whichever direction, decreased.
Organoaluminium reagents can exhibit high levels of stereo-
selectivity in their additions to aldehydes.22 Additionally, tri-
methylaluminium has been shown to be capable of forming
five-membered chelates with epoxyalcohol derivatives, increas-
ing their reactivity and controlling the regioselectivity of their
reactions.34 We therefore briefly investigated the effect of
organoaluminium reagents on the stereoselectivity of addi-
tions to chiral aldehydes. In the presence of one equivalent of
DIBAL-H, octynyllithium gave the alcohol 13d solely as its
anti-diastereoisomer (entry 9).35 The reaction was (unsurpris-
ingly) accompanied by a significant amount of reduction to
alcohol 16d and behaved unpredictably, with 16d sometimes
being the sole product.36 No reaction was observed when
DIBAL-H was replaced with trimethylaluminium. However, in
the presence of catalytic quantities (0.1 equiv.) of trimethyl-
aluminium, reactivity was restored, the anti diastereoisomer
being produced (entry 8) with slightly lower stereoselectivity
than with stoichiometric DIBAL-H. The same enhanced anti-
stereoselectivity was observed when BuLi was added to 4d in
the presence of catalytic trimethylaluminium (entry 6).
Fig. 1 Conformation of aldehyde 4.
Trialkylaluminiums cannot usually be used as Lewis acids in
the presence of organolithiums because of the rapid formation
of ate-complexes. However, Maruoka and co-workers34 have
shown that Me3Al leads to an enhancement of the reactivity of
epoxy-alcohol derivatives towards organolithiums which can-
not be ascribed to ate complex formation: catalytic quantities
of Me3Al are essential. DIBAL-H–trialkylaluminium com-
plexes have moreover been used to control the selectivity of
additions of vinyllithiums to chiral aldehydes.37 We therefore
propose that these are reactions of organolithiums catalysed
(and increased in selectivity) by coordination of R3Al to the
aldehyde oxygen, and that the presence of excess Me3Al leads to
the formation of less reactive ate complexes. The highly selec-
tive formation of the anti diastereoisomer suggests that chel-
ation between the amide and aldehyde carbonyl groups is not
involved.
As an alternative to the use of additives, we next turned
to reagents designed respectively to avoid and to promote
chelation during stereoselective reactions. Alkyltitanium tri-
isopropoxides, whose reactions with α-alkoxyaldehydes pro-
ceed via non-chelated transition states,15,38,39 were made by
treating MeLi, BuLi, octynyllithium, phenyllithium and
allylmagnesium bromide with ClTi(Oi-Pr)3. The outcomes of
their reactions with 4 are shown in entries 19–23 of Table 2.
Apart from one case, the reactions went in the same sense as
most of the organolithium reactions—they were anti-selective—
but with much higher levels of stereocontrol than even the
Me3Al-catalysed reactions (entries 6, 8 and 9). MeTi(Oi-Pr)3
was the most selective of all, reacting with 4c, 4d and 4e with
50:1, 300:1 and >99:1 selectivity respectively (entry 19), with
the octynylTi(Oi-Pr)3 performing almost as well (entry 21: the
octynyltitanium species reacts with selectivity opposite to that
of octynyllithium). BuTi(Oi-Pr)3 reacted selectively with the
Ni-Pr2 aldehyde 4d, though the selectivity with the NEt2 alde-
hyde 4c was less good (entry 20). The allyl reagent (entry 23),
as before, was less selective, and the PhTi(Oi-Pr)3 (entry 22)
exhibited a bizarre switch from anti-selectivity with 4d to syn-
selectivity with 4c [PhLi had also proved unusually syn-selective
(entry 7)].
Scheme 4
principally by the nature of the metal and are influenced rela-
tively little by the size of R1 and R2.
In contrast with the reactions of aldehydes 4 the reactions of
ketones 2 all proceed with the same stereochemical sense1
because all reagents attack 2 from the less hindered face (syn to
the amide C᎐O) of its s-cis conformation. For aldehyde 4, both
᎐
s-cis and s-trans conformations are accessible (Fig. 1), and 4
may present either face of its electrophilic carbonyl group to an
incoming reagent simply by rotation about the Ar–CHO bond.
The effect of the metal on the stereoselectivity of the reaction
could be a result of the degree of chelation by the metal
between the amide and the aldehyde carbonyl groups, which
would affect the Ar–CHO torsional angle in the transition
state.33 This being so, additives which promote or dissuade chel-
ation should influence the selectivity accordingly. We added to
the reactions of BuLi, PhLi and BuMgCl four equiv. of HMPA
The alkyltitanium triisopropoxide reactions demonstrate that
the key to good anti-selectivity in the addition to 2-formyl-1-
naphthamides is to avoid chelation. In fact, the results obtained
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(c) The results in the presence of Lewis acids BF3ؒOEt2,
MgBr2 and ZnBr2 are harder to account for. A possible general
explanation for the decrease in selectivity observed in all 8
experiments employing these additives is that Lewis acids prefer
above all to coordinate to the amide carbonyl group, which is
the most basic site in the molecule. This coordination (illus-
trated in Fig. 2(c)) increases the effective size of the C᎐O group,
᎐
lessening the steric distinction between O and NR1R2, and
decreasing the ability of the amide to direct highly selective
reactions.44
Lewis-acid mediated additions of allyltrimethylsilane to
aldehydes and acetals
An alternative way of avoiding chelation during the additions is
to use, instead of the aldehydes, the oxonium ions 20.43 These
would be made from the corresponding acetals on treatment
with Lewis acids,45 and would allow us to use allyltrimethyl-
silane as a nucleophile.46 The acetals 18 were formed straight-
forwardly from the aldehydes by refluxing with ethanol; 18a
was made directly from the bromoaldehyde 831 which was first
converted to the acetal29 and then to the amide by bromine–
lithium exchange and reaction with N,N-dimethylcarbamoyl
chloride (Scheme 5).
Fig. 2 Chelation and non-celation control in the attack of organo-
metallics on aldehydes 4.
here are among the most selective reactions ever observed for
chiral aldehydes,15 and may indeed be the most selective ever of
chiral aldehydes without an α-chiral centre. We attribute the
exceptionally high levels of stereoselectivity to co-ordination of
the bulky titanium reagent to the aldehyde as the reaction takes
place, which (along with the titanium’s lack of ability to chelate
the amide C᎐O) greatly destabilises the s-cis conformation40 of
the aldehyde. Reaction on the less hindered face of 4 then leads
Scheme 5 Synthesis of acetals 18; (i) EtOH, p-TsOH, 4 Å sieves; (ii) 1.
2 × t-BuLi, Ϫ78 ЊC, Et2O, 2. ClCONMe2.
᎐
solely to the anti diastereoisomer.
Alkyltitanium trichlorides, in contrast, favour chelation.15,16
When we treated 4c and 4d with MeTiCl3 made from MeMgBr
(entry 24) we got a moderate yield of the desired alcohols 11c
with high syn-selectivity and 11d with moderate anti-selectivity,
along with some by-product 17. When the MeTiCl3 was made
from MeLi (entry 25), the diol 17 was the only product isolated.
An X-ray crystal structure proved that 17 has an anti relation-
ship between the hydroxy-bearing centres and the respective
We treated each of the aldehydes 4a–4d and each of the
acetals 18a–18d with allyltrimethylsilane in the presence of
TiCl4 or SnCl4. To ensure completion, 2 equiv. of Lewis acid
were required with the aldehydes; one equiv. with the acetals
(Scheme 6). The results of the reactions are shown in Table 3.
Unlike the previous results, changing the reagents had no
effect on the sense of the selectivity, and relatively little effect
on the magnitude of the selectivity. The one remarkable point is
that while reactions of NMe2, NMet-Bu and NEt2 amides 4a–c
and 18a–c are all syn-selective—some highly syn-selective—all
the reactions with the Ni-Pr2 amides 4d and 18d are anti-selec-
tive. The fact that both the acetal-derived oxonium ions 20 and
the aldehydes 4 react with the same selectivity in each case
suggests that none of these reactions is under chelation con-
trol, and that the aldehyde is reacting in an extended s-trans
conformation (this is certainly expected for 20, whose s-cis con-
formation will be particularly crowded) as shown in Fig. 3. Yet
most of the reactions give the syn product—possible only if the
reagent approaches the face of the aldehyde syn to the amide
nitrogen. This could be explained if (i) the N-substituents (or at
least the one trans to O) are relatively small (Me or Et, as they
are in 4a–c) and (ii) the amide oxygen is made larger by
coordination (Fig. 3(a)). Significant complexation between the
basic amide oxygen and the strongly Lewis acidic Ti or Sn
reagents is to be expected, especially since two equivalents of
Lewis acid were needed to ensure completion in the reactions
of 4. We can then rationalise the anti-selectivity of 4d and
18d by proposing that while the Lewis-acid complexed amide
amide C᎐O groups, and is formed as a single syn diastereo-
᎐
isomer of the diol. Intramolecular pinacol couplings are rarely
stereoselective,41,42 but Seebach and Raubenheimer43 have
described the use of a low-valent titanium reagent, formed by
reduction of TiCl4 with BuLi, to carry out syn-selective pinacol
couplings. We assume a similar low-valent titanium species is
involved here.
Bearing in mind the complexity of the possible metal–amide–
aldehyde–solvent aggregates likely in the reaction mixture,
detailed speculation on the origin of each individual stereo-
selectivity is pointless. However, regarding the effect of the
metal on the stereoselectivity, we draw the following general
conclusions:
(a) Non-chelating metal atoms (Li, Ti, Al) promote reaction
through an s-trans conformation approximating to that shown
in Fig. 2(a). With Met = Ti(Oi-Pr)3 or AlMe3, the size of the
metal ligand means that this is very much the favoured con-
formation and high selectivities result.
(b) Chelating metal atoms (Mg) promote reaction through a
conformation approximating to that shown in Fig. 2(b) in
which the other face of the CHO group is exposed to attack.
C᎐O is larger than Me or Et,44 it is still less efficient at blocking
᎐
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Table 3 Lewis acid-promoted additions of allyltrimethylsilane to aldehydes and acetals
From 4a or 18a
From 4b or 18b
From 4c or 18c
From 4d or 18d
Starting
material
Lewis
acid
Product,
Ratiob
anti:syn
Product
Ratiob
anti:syn
Product,
Ratiob
anti:syn
Product,
Ratiob
anti:syn
Entry
yielda (%)
yielda (%)
yielda (%)
yielda (%)
1
2
3
4
4
18
SnCl4
TiCl4
TiCl4
15a 62c
15a 57c
21a 57
3:97
29:71
12:88
—
15b 81
21b 58
—
34:66
10:90
15c 61
15c 54
21c 73
20:80
12:88
10:90
15d 56
15d 58
21d 47
92:8
91:9
93:7
a Isolated yield. b Ratio in 1H NMR of crude product. c The crude product contained, additionally, traces of the lactone 22. 15a lactonised slowly on
standing, and 22 was formed almost quantitatively from 15a after 1 week at 60 ЊC in CDCl3.
Fig. 4 X-Ray crystal structure of anti-15c.
Fig. 3 Stereoselectivity in the additions of allyltrimethylsilane.
Fig. 5 X-Ray crystal structure of anti-15d.
δC᎐O = 165.6; tR = 6.4 min [2:1 petrol–EtOAc]) were determined
and confirm the generality of this method for stereochemical
assignment. It was therefore used to assign stereochemistry to
the diastereoisomers of the remaining alcohols 12c–12e, 13c,
13d, 15a and 15b.
Scheme 6 Reactions with allyltrimethylsilane; (i) SnCl4 or TiCl4; (ii)
allyltrimethylsilane; (iii) MeLi, Et3OϩBF4Ϫ; (iv) NaH, EtI; (v) CDCl3,
The stereochemistry of the ethers 21 was determined by con-
version of one diastereoisomer of each of the alcohols 15a–15d
(syn-15a, anti-15b, syn-15c, anti-15d) to single diastereoisomers
of the ethers 21a–21d using NaH, EtI, or, for 15a (which readily
lactonises to 22 under these conditions) MeLi and triethyl-
oxonium tetrafluoroborate.
60 ЊC.
reagent approach than i-Pr (Fig. 3(b)). The switch in selectivity
does not arise from hindrance to O-complexation by one of the
Ni-Pr groups, since 4b and 18b, with an N-t-Bu group cis to
oxygen, reacts with the opposite selectivity.
Organolithium additions to imines
Assigning the stereochemistry of the alcohols 11–15 and ethers
21
The final part of our investigation concerned the addition of
organolithiums to the imine derivatives of 2-formyl-1-naphth-
amides.5 Imines typically react with higher stereoselectivity
than their parent aldehydes,47 and we expected the imine 23, like
the oxonium ions 20, to prefer the extended s-trans conform-
ation for steric reasons. Unlike the oxonium ions, however, they
could in principle still react under chelation control. 2-Alkoxy-
imines react under chelation control with Grignards, though
their reactions with organolithiums are poorly selective.48 How-
ever, 2-(N,N-dibenzylamino)imines (unlike their parent alde-
hydes) react highly selectively under chelation control with
organolithiums.49
We have previously assigned stereochemistry to the known
alcohols 11c–e and 14c–e either by X-ray crystallography (14d)
or by a method based on polarity and 13C NMR correlations.
We noted that, for alcohols of the general structure 1, syn-1 is
the more polar of the diastereoisomers, and its C᎐O signal in
᎐
the 13C NMR is always downfield of anti-1’s C᎐O signal. The
᎐
X-ray crystal structures (shown in Figs. 4 and 5) of anti-15c
(δC᎐O = 164.6; tR = 5.9 min [2:1 petrol–EtOAc]; compare syn-
15c δC᎐O = 169.9; tR = 12.3 min [2:1 petrol–EtOAc]) and anti-15d
(δC᎐O = 164.4; tR = 3.7 min [2:1 petrol–EtOAc]; compare syn-15d
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Scheme 7 Synthesis and reactions of imine 23; (i) MeNH2, H2O, 60 min; (ii) MeLi or BuLi, Ϫ78 ЊC, 1–3 h; (iii) NH4Cl, Ϫ78 ЊC or BnBr, 0 ЊC.
Fig. 7 Stereoselectivity in the addition of organolithiums to imines.
Fig. 6 X-Ray crystal structure of syn-24.
Table 4 Addition of organolithiums to imines 23
Product,
yield (%)
Ratio
syn:anti
By-product,
yield (%)
Entry
RLi
Eϩ
1
2
3
4
MeLi
BuLi
MeLi
BuLi
NH4Cl
NH4Cl
BnBr
24 92
25 85
26 15
27 16
>96:4
92:8
96:4
92:8
—
28a
29 64
30 34
BnBr
a Trace amounts of 28 were produced.
We made the N-methylimine 23 from 4d simply by heating
the aldehyde with aqueous methylamine. The imine was then
treated with MeLi or BuLi in THF at Ϫ78 ЊC for 1–3 h and
quenched with ammonium chloride to yield the amines 24 or
25. Both of the reactions were highly selective (Table 4): it was
not possible to detect the minor diastereoisomer from the
addition of MeLi to 23. The product of this reaction, syn-24
was crystalline, and its X-ray crystal structure (Fig. 6) proved
the syn stereochemistry which we assume to be that of the
major isomer of 25 too.
Fig. 8
which was absent from the RLi–carbonyl additions, may
become important in the late transition states of the imine
additions.
We made the tertiary amines 26 and 27 in a similar way, by
quenching the reactions with BnBr. Alkylation reached comple-
tion only when the reaction mixtures were warmed to 0 ЊC for
1–3 h. The tertiary amines 26 and 27 could then be isolated in
low yield, but the major products were the lactams 29 and 30,
presumably formed by the mechanism outlined in Scheme 7,
which outpaces the N-benzylation. Traces of related lactam 28
are formed in the reactions leading to 25.
Summary
The stereoselectivity of the reactions of 2-formyl-1-naphth-
amides is very much subject to the conformational freedom
inherent in the Ar–CHO bond. Reagents which limit this free-
dom, by chelation, for example, or by coordination of Lewis
acids to the aldehyde, allow higher levels of selectivity to be
obtained. In general, we propose three models for the reactions
of aldehydes 4 and their derivatives (Fig. 8): (a), dominated by
Considering the moderate anti-selectivity shown by additions
of organolithiums to the related aldehydes 4, the syn-selectivity
in these reactions is surprising. There are two possible factors at
coordination of a Lewis acidic metal to the aldehyde C᎐O,
᎐
work here. Firstly, repulsion between Ni-Pr and CH᎐NMe is
which may lead to very high levels of selectivity in favour of the
anti isomer [aldehydes ϩ RLi, RLi–AlR3, RTi(Oi-Pr)4]; (b),
dominated by chelation of a metal ion by both carbonyl
᎐
2
greater than between Ni-Pr and CH᎐O, and may be favouring
᎐
2
a conformation approaching Fig. 7(b). Secondly, chelation,
1368
J. Chem. Soc., Perkin Trans. 1, 2000, 1363–1378

View Article Online
groups, which may lead to good selectivity for the syn isomer
[aldehydes ϩ RMgX, imines ϩ RLi]; and (c), dominated by
10.36 mmol) was added. The mixture was stirred for 5 min-
utes, warmed to ambient temperature and stirred for a further
1 hour. Saturated aqueous sodium hydrogen carbonate (10 ml)
was added and the solvent was removed under reduced pres-
sure. The aqueous phase was extracted with dichloromethane
(4 × 20 ml), and the combined organic extracts were washed
with brine (50 ml), dried (MgSO4), filtered and concentrated
under reduced pressure to give naphthamide 10 as a brown oil
which was used without further purification, νmax(film)/cmϪ1
2950, 2938, 2889, 1638; δH(300 MHz, CDCl3) 7.92 (1H, d, J 8.5,
ArH), 7.88 (1H, m, ArH), 7.75 (1H, m, ArH), 7.71 (1H, d, J 8.5,
ArH), 7.58–7.52 (2H, m, ArH), 6.00 (1H, s, CH(OCH2CH2O)),
4.30–3.90 (4H, m, CH2CH2), 3.30 (3H, s, CH3), 2.78 (3H, s,
CH3); δC(75 MHz, CDCl3) 169.5, 134.0, 133.6, 131.3, 129.0,
128.8, 128.2, 127.1, 126.8, 124.9, 123.4, 101.7, 65.7, 65.4, 38.4
and 34.5; m/z (CI) 272 (100%, M ϩ Hϩ); m/z (EI) 271 (3%, Mϩ)
and 198 (100%, M Ϫ C3H6O2) (Found: M ϩ Hϩ, 272.1294.
C16H17NO3 requires M ϩ H, 271.1208).
coordination of a Lewis acid to the amide C᎐O group, which,
᎐
leads to lowered anti-selectivity, and with small NR2 to a switch
to syn-selectivity [aldehydes ϩ RMet ϩ added Lewis acid, oxo-
nium ions ϩ allylSiMe3 ϩ Lewis acid].
Experimental
General experimental details have been given before.1
1-Bromo-2-(bromomethyl)naphthalene 7
By the method of Smith et al.29 a solution of 1-bromo-2-
methylnaphthalene (9.720 g, 43.96 mmol), N-bromosuccin-
imide (8.398 g, 47.18 mmol), benzoyl peroxide (0.200 g, 0.83
mmol) and carbon tetrachloride (100 ml) was heated to reflux
for 5.5 hours under an atmosphere of nitrogen, cooled, washed
with saturated aqueous sodium hydrogen carbonate (3 × 50
ml), dried (MgSO4), filtered and concentrated under reduced
pressure to give a yellow solid which was recrystallised from
petrol to give bromide 7 (7.920 g, 60%) as yellow needles, mp
106–107 ЊC (lit.,29 103–105 ЊC).
N,N-Dimethyl-2-formyl-1-naphthamide 4a
Toluene-p-sulfonic acid dihydrate (215 mg, 1.03 mmol) was
added to a solution of crude naphthamide 10 in acetone (50 ml)
at ambient temperature. The mixture was stirred for 11 hours.
Water (30 ml) was added and the acetone was removed under
reduced pressure. The aqueous residue was extracted with ethyl
acetate (4 × 20 ml) and the combined organic extracts were
washed with saturated aqueous sodium hydrogen carbonate
(2 × 30 ml), brine (30 ml), dried (MgSO4), filtered and concen-
trated under reduced pressure to give a yellow solid which was
recrystallised from ethyl acetate to give the aldehyde 4a (885 mg,
83%) as orange prisms, λmax/nm (εmax) (CH2Cl2) 254 (60320),
290 (10800), 340 (2475); mp 111–115 ЊC (EtOAc); νmax(film)/
cmϪ1 3240, 1689, 1633; δH(300 MHz, CDCl3) 10.22 (1H, s,
CHO), 8.00–7.85 (4H, m, ArH), 7.7–7.6 (2H, m, ArH), 3.37
(3H, s, CH3), 2.79 (3H, s, CH3); δC(75 MHz, CDCl3) 190.5,
168.3, 139.9, 136.1, 129.4, 129.3, 129.1, 129.0, 128.5, 128.0,
126.1, 123.3, 38.2 and 34.7; m/z (CI) 228 (100%, M ϩ Hϩ); m/z
(EI) 227 (6%, Mϩ), 198 (40%, M Ϫ CHO), 183 (43%, M Ϫ
CON(CH3)2), 127 (100%) (Found: C, 73.9; H, 6.04; N, 6.10%.
C14H13NO2 requires C, 74.0; H, 5.7; N, 6.2%).
1-Bromo-2-formylnaphthalene 8
By a modification of the method of Hass and Bender,30 sodium
(0.667 g, 0.029 mol) was carefully added to a flask charged with
ethanol (30 ml). When the sodium had dissolved, 2-nitro-
propane (2.85 ml, 0.032 mol) was added. A white precipitate
formed immediately. The mixture was treated with 1-bromo-2-
(bromomethyl)naphthalene 7 (7.920 g, 0.026 mol) and heated
to reflux for 6 h with occasional agitation of the reaction
vessel. The mixture was allowed to cool to ambient temper-
ature, treated with water (30 ml) and the ethanol was removed
under reduced pressure. Ether (50 ml) was added and the solu-
tion was washed with aqueous 1 M sodium hydroxide (2 × 20
ml) and water (2 × 20 ml), dried (MgSO4), filtered and concen-
trated under reduced pressure to give the crude product in
quantitative yield. Recrystallisation from EtOAc gave the alde-
hyde 8 (3.877 g, 62%) as yellow needles, mp 115–117 ЊC (lit.,29
115–116 ЊC).
2-(1-Bromo-2-naphthyl)-1,3-dioxolane 9
N-(tert-Butyl)-N-methyl-2-formyl-1-naphthamide 4b
By the method of Hartman et al.32 a solution of 1-bromo-2-
formylnaphthalene 8 (1.507 g, 6.41 mmol), ethylene glycol (0.50
ml, 8.98 mmol), toluene-p-sulfonic acid dihydrate (0.366 g, 1.92
mmol) in benzene (30 ml) was heated to reflux under a Dean–
Stark condenser overnight. The mixture was cooled, diluted
with ether (30 ml), washed with 10% aqueous sodium hydroxide
(3 × 20 ml) and water (5 × 20 ml), dried (MgSO4), filtered and
concentrated under reduced pressure to give the dioxolane 9 as
a pale yellow oil (1.636 g, 91%) requiring no further purifi-
cation, νmax(film)/cmϪ1 3065, 2953, 2886, 1788; δH(300 MHz,
CDCl3) 8.44 (1H, J 8.4, ArH), 7.92–7.85 (2H, m, ArH), 7.75
(1H, d, J 8.5, ArH), 7.70–7.56 (2H, m, ArH), 6.48 (1H, s,
CH(OCH2)2), 4.32–4.12 (4H, m, CH2CH2); δC(75 MHz,
CDCl3) 134.9, 134.5, 132.1, 128.1, 127.9, 127.5, 127.1, 124.1,
123.9, 103.4, 103.4 and 65.6; m/z (CI) 279 (100%, M ϩ Hϩ)
and 281 (86%, M ϩ Hϩ); m/z (EI) 278 (13%, Mϩ[79Br]), 280
(13%, Mϩ[81Br]), 73 (100%, CH(OCH2)2) and 199 (42%,
M Ϫ 79Br) (Found: Mϩ, 277.9942. C13H11O2Br requires M,
277.9943).
sec-Butyllithium (5.68 ml, 7.39 mmol; 1.3 M solution in hex-
anes) was added to a solution of naphthamide 3b28 (1.619 g,
6.72 mmol) in THF (50 ml) at Ϫ78 ЊC under an atmosphere
of nitrogen. After 1 h, DMF (1.0 ml, 12.9 mmol) was added.
The mixture was allowed to warm to ambient temperature,
quenched with water (20 ml) and stirred overnight. The THF
was removed under reduced pressure and the aqueous residue
was diluted with ether (60 ml). The layers were separated
and the ethereal layer was washed with water (4 × 30 ml), dried
(MgSO4), filtered and concentrated under reduced pressure
to afford the crude product mixture. Purification by flash
chromatography on silica gel [10:1 petrol–EtOAc] afforded
the aldehyde 4b (602 mg, 33%) as a colourless oil which
solidified on standing, mp 122–124 ЊC; Rf 0.31 [2:1 petrol–
EtOAc]; νmax(film)/cmϪ1 2963, 2927, 2871, 2850, 1690, 1633;
δH(300 MHz, CDCl3) 10.27 (1H, s, CHO), 8.00–7.88 (4H, m,
ArH), 7.70–7.59 (2H, m, ArH), 2.74 (3H, s, NCH3), 1.72 (9H,
s, C(CH3)3); δC(75 MHz, CDCl3) 190.6, 168.5, 142.5, 136.3,
129.3, 128.8, 128.7, 128.4, 127.9, 125.8, 122.8, 58.0, 33.9 and
28.0; m/z (CI) 270 (100%, M ϩ Hϩ); m/z (EI) 269 (2%, Mϩ),
212 (100%, M Ϫ t-Bu) and 183 (94%, M Ϫ N(t-Bu)Me)
(Found: M ϩ Hϩ, 270.1493. C17H19NO2 requires M ϩ H,
270.1494).
N,N-Dimethyl-2-(1,3-dioxolan-2-yl)-1-naphthamide 10
A solution of dioxolane 9 (1.314 g, 4.71 mmol) in ether (30 ml)
was added dropwise to a solution of tert-butyllithium (6.09 ml,
10.36 mmol) in ether (50 ml) at Ϫ78 ЊC under an atmosphere of
nitrogen to give an orange–brown solution. The mixture was
stirred for an additional 35 minutes, by which time a precipi-
tate had formed. N,N-Dimethylcarbamoyl chloride (0.96 ml,
Also obtained was N-(tert-butyl)-N-methyl-2-(1-methyl-
propyl)-1,2-dihydro-1-naphthamide 5 (1.306 g, 65%) as a brown
oil, which contained a mixture of diastereoisomers in a ratio of
56a :23b :10c:7d (by 1H NMR), Rf 0.31 [10:1 petrol–EtOAc];
J. Chem. Soc., Perkin Trans. 1, 2000, 1363–1378
1369

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νmax(film)/cmϪ1 3028, 2959, 2926, 2873, 1649; δH(300 MHz,
CDCl3) 7.31–6.93 (4H, m, ArH), 6.58 (1Ha, d, J 10,
CH᎐CHCH), 6.52 (1Hc, d, J 10, CH᎐CHCH), 6.51 (1Hb, d, J
amide anti-12c as a white solid, mp 85–88 ЊC; Rf 0.32 [2:1
petrol–EtOAc]; tR 8.4 min [2:1 petrol–EtOAc]; νmax(film)/cmϪ1
3425 (OH), 1613 (C᎐O); δH(300 MHz, CDCl3) 8.0–7.4
᎐
᎐
᎐
10, CH᎐CHCH), 6.50 (1Hd, d, J 10, CH᎐CHCH), 6.04 (1Hd,
(6H, m, ArH), 4.83 (1H, dd, J 7.5 and 7.5, CH(OH)), 3.77
(1H, m, J 7.5, NCHAHB), 3.73 (1H, m, NCHAHB), 3.14 (1H,
m, NCHAHB), 3.12 (1H, m, NCHAHB), 2.8 (1H, br m, OH),
1.86 (2H, m, CH(OH)CH2), 1.6–1.3 (4H, m, CH2CH2), 1.43
(3H, t, J 7.5, NCH2CH3), 0.96 (3H, t, J 7.5, NCH2CH3),
0.91 (3H, t, J 7.5, CH2CH2CH3); δC(75 MHz, CDCl3) 169.3
(CONEt2), 138.0, 132.8, 131.8, 129.4, 129.0, 128.1, 126.9,
126.2, 125.0, 123.6 (aromatics), 72.4 (CHOH), 43.2, 39.0,
38.8, 28.1, 22.6, 14.1 (2 peaks) and 12.9 (NEt2 and n-butyl);
m/z (CI) 314 (100%, M ϩ Hϩ) and 296 (30%, M Ϫ OH); m/z
(EI) 313 (8%, Mϩ) (Found: Mϩ, 313.2040. C20H27NO2 requires
M, 313.2042).
᎐
᎐
dd, J 10 and 4, CH᎐CHCH), 5.97 (1Ha, dd, J 10 and 5, CH᎐
᎐
᎐
CHCH), 5.93 (1Hb, dd, J 10 and 2.5, CH᎐CHCH), 4.42 (1Ha, d,
᎐
J 7.5, CHCON(t-Bu)CH3), 4.33 (1Hc, d, J 7.5, CHCON-
(t-Bu)CH3), 4.12 (1Hd, d, J 11.5, CHCON(t-Bu)CH3), 4.10
(1Hb, d, J 13, CHCON(t-Bu)CH3), 3.14 (3Hc, s, NCH3), 3.09
(3Ha, s, NCH3), 3.02 (3Hb, s, NCH3), 3.01 (3Hd, s, NCH3), 2.70
(1H, m, CH᎐CHCH), 1.82 (1H, m, CH CH CH(CH )), 1.56
᎐
3
2
3
(9Hb, s, t-Bu), 1.54 (9Hd, s, t-Bu), 1.51 (9Ha, s, t-Bu), 1.45 (9Hc,
s, t-Bu), 1.5–1.2 (2Hb,c,d, m, CH3CH2), 0.94 (3Ha, t, J 7.5,
CH3CH2), 0.75 (3Ha, d, J 6.5, CH3CH2CH(CH3)); δC(75 MHz,
CDCl3) 172.6, 134.9, 133.9, 129.5, 128.2, 128.1, 127.5, 127.3,
127.1, 127.0, 126.8, 126.6, 126.3, 126.1, 125.9, 125.6, 57.2, 47.5,
45.8, 42.7, 41.7, 40.2, 36.4, 35.8, 32.3, 28.3, 28.2, 27.6, 27.6,
25.1, 15.4, 15.3, 12.1 and 11.9; m/z (CI) 300 (100%, M ϩ Hϩ);
m/z (EI) 299 (3%, Mϩ) and 57 (100%) (Found: Mϩ, 299.2248.
C20H29NO requires M, 299.2249).
Also obtained was (Ra*S*)-N,N-diethyl-2-(1Ј-hydroxy-
pentyl)-1-naphthamide syn-12c as a colourless oil, Rf 027 [2:1
petrol–EtOAc]; tR 13.3 min [2:1 petrol–EtOAc]; νmax(film)/cmϪ1
3417 (OH), 1613 (C᎐O); δ (300 MHz, CDCl ) 7.9–7.4 (6H,
᎐
H
3
m, ArH), 4.79 (1H, dd, J 7.5 and 9.5, CHOH), 3.31 (1H, m,
NCHAHB), 3.22 (1H, m, NCHAHB), 3.10 (2H, q, J 7.5, NCH2),
2.05 (1H, m, CH(OH)CHAHB), 1.79 (1H, m, CH(OH)CHAHB),
1.5–1.3 (4H, m, CH2CH2), 1.42 (3H, t, J 7.5, NCH2CH3), 1.00
(3H, t, J 7.5, NCH2CH3), 0.95 (3H, t, J 7.5, CH2CH2CH3);
δC(75 MHz, CDCl3) 170.0 (CONEt2), 138.6, 132.7, 132.6,
129.2, 129.1, 128.3, 126.9, 126.2, 124.8, 123.8 (aromatics), 71.0
(CHOH), 43.2, 38.7, 35.8, 28.6, 22.7, 14.1, 13.8 and 12.8 (NEt2
and n-butyl); m/z (CI) 314 (75%, M ϩ Hϩ) and 296 (M Ϫ OH);
m/z (EI) 313 (17%, Mϩ) (Found: Mϩ, 313.2038. C20H27NO2
requires M, 313.2042).
N,N-Diethyl-2-formyl-1-naphthamide 4c
A solution of N,N-diethyl-1-naphthamide 3c2 (3.189 g, 14.03
mmol) in THF (40 ml) was added to a stirred solution of sec-
butyllithium (11.85 ml of a 1.3 M solution in cyclohexane,
15.44 mmol) in THF (80 ml) at Ϫ78 ЊC under an atmosphere
of nitrogen. After 1 hour at Ϫ78 ЊC, the mixture was treated
with a solution of DMF (5.24 ml) in THF (20 ml) and allowed
to warm to ambient temperature. Water (50 ml) was added and
most of the THF was removed under reduced pressure. The
residue was extracted with dichloromethane (3 × 50 ml). The
combined organic fractions were washed with brine, dried
(MgSO4) and evaporated under reduced pressure at room tem-
perature. Flash chromatography [4:1 petrol–EtOAc] afforded
the aldehyde 4c as a pale yellow solid (2.771 g, 78%), mp 65–
66 ЊC; Rf 0.23 [2:1 petrol–EtOAc]; νmax(film)/cmϪ1 1697,
1630; δH(200 MHz, CDCl3) 10.21 (1H, s, CHO), 8.0–7.5 (6H,
m, ArH), 3.77 (2H, q, J 7.5, NCH2), 3.06 (2H, q, J 7.5, NCH2),
1 43 (3H, t, J 7.5, CH3), 0.95 (3H, t, J 7.5, CH3); δC(75 MHz,
CDCl3) 190.6 (CHO), 167.4 (CONEt2), 140.8, 136.2, 129.5,
129.3, 129.1, 128.6, 127.9, 126.1, 122.8 (aromatics), 43.2 (CH2),
39.3 (CH2), 14.0 (CH3) and 12.9 (CH3); m/z (CI) 256 (100%,
M ϩ Hϩ); m/z (EI) 255 (4%, Mϩ) and 226 (100%, M Ϫ Et)
(Found: M ϩ Hϩ, 256.1332. C16H17NO2 requires M, 256.1337).
Similarly, aldehyde 4d28 gave (Ra*R*)-N,N-diisopropyl-2-
(1Ј-hydroxypentyl)-1-naphthamide anti-12d as a white solid,
mp 117–119 ЊC, Rf 0.47 [2:1 petrol–EtOAc]; tR 5.4 min [4:1
petrol–EtOAc]; νmax(film)/cmϪ1 3436 (OH), 1612 (C᎐O); δ (200
᎐
H
MHz, CDCl3) 7.9–7.4 (6H, m, ArH), 4.91 (1H, t, J 7.5,
CHOH), 3.65 (1H, septet, J 7.5, NCH), 3.63 (1H, septet, J 7.5,
NCH), 2.21 (1H, br s, OH), 1.88 (2H, m, CH(OH)CH2), 1.82
(3H, d, J 7.5, NCHCH3), 1.73 (3H, d, J 7.5, NCHCH3), 1.51–
1.38 (4H, m, CH2CH2), 1.17 (3H, d, J 7.5, NCHCH3), 1.03 (3H,
d, J 7.5, NCHCH3), 0.93 (3H, t, J 7.5, CH2CH3); δC(75 MHz,
CDCl3) 169.0 (CONiPr2), 137.4, 133.1, 132.9, 129.4, 128.6,
128.1, 126.7, 126.2, 125.2, 123.4 (aromatics), 72.0 (CHOH),
51.1 (NCH), 46.2 (NCH), 38.9, 28.1, 22.5, 20.9, 20.7, 20.6, 20.4
and 14.0 (4 × CH3 and n-butyl); m/z (CI) 342 (100%, M ϩ Hϩ)
and 324 (M Ϫ OH); m/z (EI) 341 (18%, Mϩ) (Found: Mϩ,
341.2357. C22H31NO2 requires M, 341.2355).
Also obtained was (Ra*S*)-N,N-diisopropyl-2-(1Ј-hydroxy-
pentyl)-1-naphthamide syn-12d as a white solid, mp 99–102 ЊC;
Rf 0.39 [2:1 petrol–EtOAc]; tR 7.5 min [4:1 petrol–EtOAc];
General procedure for reaction of aldehydes 4 with organolithium
or Grignard reagents
A solution of the organolithium or Grignard reagent (0.98
mmol, 1.25 equiv.) was added dropwise to a stirred solution of
the aldehyde 4 (0.784 mmol) in dry THF (5 ml) under nitrogen
at Ϫ78 ЊC. After 3 hours, saturated aqueous ammonium chlor-
ide (5 ml) was added. The layers were separated and the aque-
ous layer extracted with diethyl ether (2 × 5 ml). The combined
organic fractions were washed with brine, dried (MgSO4) and
evaporated under reduced pressure without external heating.
The crude product was stored in the freezer. Analytical HPLC
[1:1–8:1 petrol or hexane–EtOAc] of the crude product gave
the diastereoisomeric ratios shown in Table 2; flash chromato-
graphy gave the purified products in the yields shown in Table 2,
and (where necessary) preparative HPLC afforded the pure
separated diastereoisomers.
In this way, with MeLi (1.4 M in Et2O) or with MeMgBr
(3 M in Et2O, aldehyde 4c gave the alcohols 11c,2 aldehyde 4d28
gave the alcohols 11d,2 and the aldehyde 4e2 gave the alcohol
anti-11e.2
In the same way, with BuLi (1.6 M in hexane), with BuMgCl
(2.0 M in THF), or with BuMgBr (2.0 M in THF) aldehyde
4c gave (Ra*R*)-N,N-diethyl-2-(1Ј-hydroxypentyl)-1-naphth-
νmax(film)/cmϪ1 3418 (OH), 1611 (C᎐O); δ (300 MHz, CDCl )
᎐
H
3
7.9–7.4 (6H, m, ArH), 4.85 (1H, dd, J 9 and 6, CHOH), 3.68
(1H, septet, J 7, NCH), 3.61 (1H, septet, J 7, NCH), 2.12 (1H,
m, CH(OH)CHAHB), 1.9–1.7 (2H, m, CH(OH)CHAHBCHC-
HD), 1.81 (3H, d, J 7.5, NCHCH3), 1.75 (3H, d, J 7.5,
NCHCH3), 1.46 (3H, m, CHCHDCH2), 1.11 (6H, d, J 7.5,
NCH(CH3)2), 0.98 (3H, t, J 7, CH2CH3); δC(75 MHz, CDCl3)
170.2 (CONiPr2), 137.8, 134.2, 132.8, 129.2, 128.8, 128.2, 126.7,
126.3, 124.9, 123.7 (aromatics), 71.0 (CHOH), 51.4, 46.4, 35.0,
28.9, 22.8, 20.9, 20.6, 20.5 and 14.1 (4 × CH3 and n-butyl);
m/z (CI) 342 (9%, M ϩ Hϩ) and 324 (M Ϫ OH); m/z (EI) 341
(15%, Mϩ) (Found: Mϩ, 341.2355. C22H31NO2 requires M,
341.2355).
Similarly, the aldehyde 4e2 gave (Ra*,1ЈS*)-N,N-di(4-
heptyl)-2-(1Ј-hydroxypentyl)-1-naphthamide anti-12e as an oil,
Rf 0.73 [2:1 petrol–EtOAc]; tR 8.3 min [6:1 hexane–EtOAc];
νmax(film)/cmϪ1 3384, 2958, 2932, 2871, 1605; δH(300 MHz,
CDCl3) 7.9–7.4 (6H, m, ArH), 4.98 (1H, dd, J 4 and 9, CHOH),
3.03 (2H, quintet, J 6.5, 2 × NCH), 2.5–0.6 (22H, m, CH(OH)-
CH2CH2CH2CH3 and 2 × NCH(CH2CH2CH3)2), 1.05 (3H, t,
J 7.5, CH3), 1.01 (3H, t, J 7.5, CH3), 0.91 (3H, t, J 7.0, CH3),
1370
J. Chem. Soc., Perkin Trans. 1, 2000, 1363–1378

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0.75 (3H, t, J 7.5, CH3), 0.36 (3H, t, J 7.5, CH3); δC(75 MHz,
CDCl3) 169.4, 138.4, 132.6, 132.1, 129.3, 128.5, 127.9, 126.1,
125.9, 125.6, 123.1, 71.8, 59.9, 56.8, 39.3, 36.9, 36.7, 35.8, 28.0,
22.3, 21.7, 20.3, 20.2, 14.4, 14.0, 14.0 and 13.2; m/z (CI) 454
(100%, M ϩ Hϩ) and 436 (17%, M Ϫ OH); m/z (EI) 453 (3%,
Mϩ) and 84 (100%) (Found: Mϩ, 453.3596. C30H47NO2 requires
M, 453.3607).
MHz, CDCl3) 7.89 (1H, d, J 8.7, ArH), 7.8 (3H, m, ArH), 7.51
(2H, m, ArH), 5.65 (1H, d, J 1.5, CHOH), 4.07 (1H, d, J 1.5,
OH), 3.64 (1H, septet, J 6.5, NCH), 3.54 (1H, septet, J 6.5,
NCH), 2.29 (2H, td, J 7.0 and 1.9, CCCH2(CH2)4CH3), 1.78
(3H, d, J 7, CH3), 1.69 (3H, d, J 7, CH3), 1.55 (2H, m,
CH2CH2(CH2)3CH3), 1.48–1.22 (6H, m, CH2CH2(CH2)3CH3),
1.10 (3H, d, J 6.5, CH3), 1.04 (3H, d, J 6.5, CH3), 0.89 (3H, t,
J 7.0, (CH2)5CH3); δC(75 MHz, CDCl3) 169.4, 135.3, 133.2,
132.9, 128.8, 128.7, 128.2, 126.7, 126.4, 125.0, 124.8, 87.8, 79.0,
62.3, 51.4, 46.4, 31.2, 28.5, 28.4, 22.4, 20.8, 20.5, 20.5, 20.4, 18.8
and 13.9; m/z (CI) 394 (13%, M ϩ Hϩ), 276 (100%, M Ϫ OH)
and 284 (64%, M Ϫ CC(CH2)5CH3) (Found: Mϩ, 393.2662.
C26H35NO2 requires M, 393.2668).
In the same way, with PhLi (1.8 M in hexane–ether) or with
PhMgBr (1.0 M in THF), aldehyde 4c gave the alcohols 14c,2
the aldehyde 4d28 gave the alcohols 14d2 and the aldehyde 4e2
gave the alcohol syn-14e.2
In the same way, with allylMgBr (1.0 M in THF) the alde-
hyde 4c gave (Ra*R*)-N,N-diethyl-2-(1Ј-hydroxybut-3Ј-enyl)-
1-naphthamide anti-15c as a white solid, mp 107–110 ЊC; Rf 0.55
(EtOAc); tR 5.9 min [2:1 petrol–EtOAc]; νmax(film)/cmϪ1 3402
Also obtained was (Ra*,1ЈR*)-N,N-di(4-heptyl)-2-(1Ј-
hydroxypentyl)-1-naphthamide syn-12e as a colourless oil, Rf
0.69 [2:1 petrol–EtOAc]; tR 21.7 min [6:1 hexane–EtOAc];
νmax(film)/cmϪ1 3408, 2958, 2932, 2871, 1605; δH(300 MHz,
CDCl3) 7.9–7.4 (6H, m, ArH), 4.88 (1H, dd, J 3.5 and 9.5,
CHOH), 3.05 (2H, m, 2 × NCH), 2.35 (2H, m, NCHCH2-
CH2CH3), 2.11 (2H, m, CH(OH)CHAHBCH2 and NCHCHA-
HBCH2CH3), 1.94 (1H, m, NCHCCHAHBCH2CH3), 1.79 (1H,
m, CH(OH)CHAHBCH2CH2CH3), 1.73–0.53 (16H, m, CH-
(OH)CH2CH2CH2CH3, 2 × NCHCH2CH2CH3, 4 × NCHCH2-
CH2CH3), 1.05 (3H, t, J 7.5, CH3), 1.01 (3H, t, J 7.5, CH3), 0.97
(3H, t, J 7.5, CH3), 0.65 (3H, t, J 7, CH3), 0.50 (3H, t, J 7, CH3);
δC(75 MHz, CDCl3) 171.0, 138.6, 134.1, 132.4, 129.3, 128.9,
128.1, 126.3, 126.1, 125.0, 123.3, 70.7, 60.4, 57.2, 36.9, 36.8,
36.4, 35.4, 33.5, 28.9, 22.8, 21.7, 20.4, 20.3, 14.4, 14.1, 13.7 and
13.5; m/z (CI) 454 (14%, M ϩ Hϩ), 438 (100%, M Ϫ CH3)
and 436 (51%, M Ϫ OH) (Found: Mϩ, 453.3596. C30H47NO2
requires M, 453.3607).
(OH), 1611 (C᎐O); δ (300 MHz, CDCl ) 7.8–7.4 (6H, m,
᎐
H
3
ArH), 5.80 (1H, m, CH CH᎐CH ), 5.14 (1H, d, J 17.5,
᎐
2
2
CH CH᎐CHtransH), 5.12 (1H, d, J 10, CH CH᎐CHHcis), 4.74
᎐
᎐
2
(1H, t, J 3.5, CHOH), 3.63 (2H, ABX3, JAX2 = JBX = 7, NCH2),
Also obtained was N,N-di(4-heptyl)-2-(hydroxymethyl)-1-
naphthamide 16 as a colourless oil, Rf 0.53 [2:1 petrol–EtOAc];
tR 2.9 min [6:1 hexane–EtOAc]; νmax(film)/cmϪ1 3412, 2959,
2932, 2871, 1603; δH(300 MHz, CDCl3) 7.88–7.78 (3H, m,
ArH), 7.57–7.45 (3H, m, ArH), 4.91 (1H, d, J 12, CHAHBOH),
4.54 (1H, d, J 12, CHAHBOH), 3.10–2.92 (2H, m, 2 × NCH),
2.09 (1H, m, NCHCHAHBCH2CH3), 1.90 (1H, m, NCHCHAHB-
CH2CH3), 1.64–0.80 (13H, m, 3 × NCHCH2CH2CH3, 3 ×
NCHCH2CH2CH3 and NCHCH2CHAHBCH3), 1.06 (3H, t,
J 7, NCHCH2CH2CH3), 1.01 (3H, t, J 7.5, NCHCH2CH2CH3),
0.92 (1H, m, NCHCH2CHAHBCH3), 0.64 (3H, t, J 7, NCH-
CH2CH2CH3), 0.43 (3H, t, J 7, NCHCH2CH2CH3); δC(75
MHz, CDCl3) 170.6, 135.4, 133.8, 132.5, 129.3, 128.9, 128.1,
127.1, 126.3, 126.2, 125.0, 63.9, 60.1, 57.0, 37.0, 36.8, 36.2, 34.9,
21.7, 20.2, 20.0, 14.4, 13.7 and 13.3; m/z (CI) 398 (20%,
M ϩ Hϩ) and 382 (100%, M Ϫ CH3); m/z (EI) 397 (1%, Mϩ), 86
(100%), 84 (100%) and 49 (100%) (Found: M ϩ Hϩ, 398.3055.
C26H39NO2 requires M ϩ H, 398.3059).
3.00 (2H, m, NCH ), 2.62 (1H, m, CH H CH᎐CH ), 2.47
᎐
2 A B 2
(1H, br s, OH), 2.37 (1H, m, CH H CH᎐CH ), 1.31 (3H,
᎐
A
B
2
t, J 7, CH3), 0.86 (3H, t, J 7, CH3); δC(75 MHz, CDCl3)
164.6 (CONEt2), 132.5, 130.1, 128.3, 127.3, 124.8, 124.4,
123.7, 122.5, 121.7, 120.4, 119.0, 114.5 (Ar and C᎐C), 66.1
᎐
(CHOH), 39.4, 38.7, 34.5 (CH2), 9.5 (CH3) and 8.4 (CH3); m/z
(CI) 298 (37%, M ϩ Hϩ) and 280 (M Ϫ OH); m/z (EI) 297
(1%, Mϩ) (Found: Mϩ, 297.1735. C22H27NO2 requires M,
297.1729).
Also obtained was (Ra*S*)-N,N-diethyl-2-(1Ј-hydroxybut-
3Ј-enyl)-1-naphthamide syn-15c as a colourless oil, Rf 0.54
[EtOAc]; tR 12.3 min [2:1 petrol–EtOAc]; νmax(film)/cmϪ1 3407
(OH), 1610 (C᎐O); δ (300 MHz, CDCl ) 7.9–7.4 (6H, m, ArH),
᎐
H
3
5.88 (1H, ddt, J 17.5, 11 and 7, CH CH᎐CH ), 5.17 (1H, dd,
᎐
2
2
J 17.5 and 2, CH CH᎐CHtransH), 5.09 (1H, d, J 10, CH CH᎐
᎐
᎐
2
2
CHHcis), 4.87 (1H, t, J 5.5, CHOH), 3.80 (1H, m, NCHAHB-
CH3), 3.71 (1H, m, NCHAHBCH3), 3.65 (1H, br s, OH), 3.09
(2H, m, NCH ), 2.78 (1H, m, CH H CH᎐CH ), 2.60 (1H, m,
᎐
2
A
B
2
Also obtained was remaining starting material 4e (30%).
In the same way, with octynyllithium, prepared from oct-1-
yne (0.15 ml, 0.98 mmol, 1.3 equiv.) in THF (0.5 ml) and n-BuLi
(0.57 ml of a 1.6 M solution in hexanes, 0.91 mmol, 1.2 equiv.)
at Ϫ78 ЊC stirred together for 30 min and added to the solution
of the aldehyde by a cannula, aldehyde 4d2 gave (Ra*,1ЈR*)-
N,N-diisopropyl-2-(1Ј-hydroxynon-2Ј-ynyl)-1-naphthamide
anti-13d as a colourless oil, Rf 0.51 [2:1 petrol–EtOAc]; tR 5.1
min [4:1 hexane–EtOAc]; νmax/cmϪ1 3388, 3057, 2959, 2931,
2870, 2858, 1612; δH(300 MHz, CDCl3) 7.84 (3H, m, ArH), 7.77
(1H, d, J 8.5, ArH), 7.50 (2H, m, ArH), 5.64 (1H, m, OH), 3.57
(2H, m, 2 × NCH), 2.87 (1H, d, J 5, CHOH), 2.23 (2H, td, J 7.0
CH H CH᎐CH ), 1.40 (3H, t, J 7, CH CH ), 0.98 (3H, t, J 7,
᎐
A B 2 2 3
CH2CH3); δC(75 MHz, CDCl3) 169.9 (CONEt2), 137.7, 134.8,
132.7, 129.2, 129.1, 128.3, 126.9, 126.3, 124.8, 123.8, 117.5 (Ar
and C᎐C), 70.8 (CHOH), 43.3, 40.6, 38.6 (CH ), 13.8 (CH ) and
᎐
2
3
12.8 (CH3); m/z (CI) 298 (64%, M ϩ Hϩ), 256 (M Ϫ C3H5)
and 280 (M Ϫ OH); m/z (EI) 297 (3%, Mϩ) (Found: Mϩ,
297.1735. C22H27NO2 requires M, 297.1729).
Similarly, the aldehyde 4d28 gave the alcohol (Ra*R*)-N,N-
diisopropyl-2-(1Ј-hydroxybut-3Ј-enyl)-1-naphthamide anti-15d
as a white solid, mp 135–139 ЊC; Rf 0.53 [1:1 petrol–EtOAc]; tR
3.7 min [2:1 petrol–EtOAc]; νmax(film)/cmϪ1 3421 (OH), 1611
(C᎐O); δ (300 MHz, CDCl ) 7.9–7.4 (6H, m, ArH), 5.91 (1H,
᎐
H
3
m, CH CH᎐CH ), 5.27 (1H, d, J 17, CH CH᎐CHtransH), 5.23
᎐ ᎐
2 2 2
᎐
and 1.9, C᎐CCH (CH ) CH ), 1.77 (3H, d, J 7, NCHCH ), 1.69
᎐
2
2
4
3
3
(3H, d, J 7, NCHCH3), 1.51 (2H, m, CH2CH2(CH2)3CH3),
1.43–1.19 (6H, m, (CH2)3CH3), 1.12 (3H, d, J 6.5, NCHCH3),
0.98 (3H, d, J 6.5, NCHCH3), 0.89 (3H, t, J 6.5, (CH2)5CH3);
δC(75 MHz, CDCl3) 168.8, 134.2, 133.6, 133.0, 129.4, 128.6,
128.0, 126.6, 126.4, 125.3, 125.0, 87.9, 80.3, 62.8, 51.2, 46.2,
31.2, 28.5, 28.4, 22.4, 20.7, 20.4, 20.4, 20.3, 18.9 and 13.9;
m/z (CI) 394 (27%, M ϩ Hϩ), 376 (100%, M Ϫ OH) and 284
(1H, d, J 9.5, CH CH᎐CHHcis), 4.95 (1H, dd, J 3.5 and 3,
᎐
2
CHOH), 3.62 (2H, septet, J 6.5, 2 × NCH), 2.75 (1H, m,
CH H CH᎐CH ), 2.46 (2H, m, OH and CH H CH᎐CH ),
᎐
᎐
A
B
2
A
B
2
1.79 (3H, d, J 6.5, CH3), 1.70 (3H, d, J 6.5, CH3), 1.13 (3H, d,
J 6.5, CH3), 1.03 (3H, d, J 6.5, CH3); δC(75 MHz, CDCl3) 164.4
(CONiPr2), 131.9, 130.3, 128.6, 128.4, 124.8, 124.0, 123.6,
122.2, 121.7, 120.5 (Ar), 118.9, 114.4 (C᎐C), 66.0 (CHOH), 46.7
᎐
ϩ
᎐
(87%, M Ϫ C᎐C(CH ) CH ) (Found: M , 393.2673. C H -
(CH2), 41.6 (NCH), 39.5 (NCH), 16.5 (CH3), 16.2 (CH3), 16.1
(CH3) and 15.9 (CH3); m/z (CI) 326 (33%, M ϩ Hϩ), 284
(M Ϫ C3H5) and 280 (M Ϫ OH); m/z (EI) 325 (2%, Mϩ)
(Found: Mϩ, 325.2043. C22H27NO2 requires M, 325.2042).
Also obtained was the alcohol (Ra*S*)-N,N-diisopropyl-2-
(1Ј-hydroxybut-3Ј-enyl)-1-naphthamide syn-15d as a colourless
oil, Rf 0.47 [1:1 petrol–EtOAc]; tR 6.4 min [2:1 petrol–EtOAc];
᎐
2
5
3
26 35
NO2 requires M, 393.2668).
Also obtained was (Ra*,1ЈS*)-N,N-diisopropyl-2-(1Ј-
hydroxynon-2Ј-ynyl)-1-naphthamide syn-13d as a white solid,
mp 90–92 ЊC; Rf 0.39 [2:1 petrol–EtOAc]; tR 12.1 min [4:1
hexane–EtOAc]; λmax/nm (εmax) (CH2Cl2) 234 (66630), 282
(7965); νmax/cmϪ1 3312, 2960, 2931, 2870, 2858, 1608; δH(300
J. Chem. Soc., Perkin Trans. 1, 2000, 1363–1378
1371

View Article Online
νmax(film)/cmϪ1 3398 (OH), 1608 (C᎐O); δ (300 MHz, CDCl )
General procedure for the addition of alkyltitanium
triisopropoxides
᎐
H
3
7.9–7.4 (6H, m, ArH), 5.97 (1H, ddt, J 17, 10 and 7,
CH CH᎐CH ), 5.23 (1H, dd, J 17 and 1.5, CH CH᎐CHtransH),
᎐
᎐
2
2
2
Chlorotitanium triisopropoxide (0.41 ml, 0.41 mmol; 1 M solu-
tion in dichloromethane) was added to a solution of alkyl-
lithium or Grignard reagent (0.37 mmol) in THF (2.4 ml) at
Ϫ78 ЊC under an atmosphere of nitrogen. The mixture was
allowed to warm to 0 ЊC, treated with a solution of aldehyde 4
(0.27 mmol) in THF (1.7 ml) and stirred for a further 4 hours.
The mixture was poured into ice-cold aqueous 2 M hydro-
chloric acid (15 ml) and diethyl ether (30 ml). Most of the
solvent was removed under reduced pressure without external
heating, and the aqueous residue was extracted with dichloro-
methane (5 × 20 ml). The combined organic extracts were dried
(MgSO4), filtered and concentrated under reduced pressure
without external heating to give the crude product. Analytical
HPLC [2:1 hexane–EtOAc] gave the diastereoisomeric ratios
(see Table 2), and the crude product was purified by flash
chromatography on silica gel [2:1 petrol–EtOAc] to give the
product alcohols in the yields shown in Table 2.
In this way, with methyllithium (1.4 M solution in ether) the
aldehyde 4c gave alcohols 11c; aldehyde 4d gave alcohols 11d
and aldehyde 4e gave alcohols 11e.
Similarly, with n-butyllithium (0.44 ml, 0.70 mmol; 1.6 M
solution in ether), aldehyde 4c gave alcohols 12c and aldehyde
4d gave alcohols 12d.
Similarly, with oct-1-ynyllithium, prepared as described
above, aldehyde 4d gave the alcohols 13d and aldehyde 4c gave
(Ra*,1ЈR*)-N,N-diethyl-2-(1Ј-hydroxynon-2Ј-ynyl)-1-naphth-
amide anti-13c as a pale yellow oil, Rf 0.23 [2:1 petrol–EtOAc];
tR 5.2 [2:1 hexane–EtOAc]; νmax/cmϪ1 3378, 3057, 2954, 2932,
2869, 2858, 1612; δH(300 MHz, CDCl3) 7.78 (2H, m, ArH), 7.70
(1H, m, ArH), 7.62 (1H, d, J 8.5, ArH), 7.43 (2H, m, ArH), 5.49
(1H, br m, CHOH), 3.80–3.55 (2H, m, CH2CH3), 3.35 (1H,
5.14 (1H, d, J 10, CH CH᎐CHHcis), 4.93 (1H, t, J 5, CHOH),
᎐
2
3.76 (1H, br s, OH), 3.63 (2H, m, 2 × NCH), 2.88 (1H, m,
CH H CH᎐CH ), 2.62 (1H, m, CH H CH᎐CH ), 1.79 (3H, d,
᎐
᎐
A
B
2
A
B
2
J 7, CH3), 1.66 (3H, d, J 7, CH3), 1.09 (6H, m, 2 × CH3); δC(75
MHz, CDCl3) 165.6 (CONiPr2), 132.5, 130.5, 129.7, 128.4,
124.7, 124.3, 123.7, 122.3, 121.9, 120.4 (Ar), 119.3, 112.9 (C᎐C),
᎐
66.1 (CHOH), 46.9 (CH2), 42.0 (NCH), 35.4 (NCH), 16.4
(CH3), 16.1 (CH3), 16.1 (CH3) and 16.0 (CH3); m/z (CI) 326
(64%, M ϩ Hϩ), 284 (M Ϫ C3H5) and 280 (M Ϫ OH); m/z (EI)
325 (7%, Mϩ) (Found: Mϩ, 325.2042. C22H27NO2 requires M,
325.2042).
General procedure for addition of organolithium or Grignard
reagents in the presence of hexamethylphosphoramide or boron
trifluoride–diethyl ether
Hexamethylphosphoramide (0.55 ml, 3.136 mmol) or boron
trifluoride–diethyl ether (0.10 ml, 0.784 mmol) was added
dropwise to a stirred solution of the aldehyde 4 (200 mg, 0.784
mmol) and in dry THF (5 ml) under nitrogen at Ϫ78 ЊC. After
40 minutes at Ϫ78 ЊC, a solution of organolithium or Grignard
reagent (0.94 mmol) was added dropwise. After 3 hours at
Ϫ78 ЊC, saturated aqueous ammonium chloride (5 ml) was
added and the products were analysed and purified as described
above.
General procedure for addition of Grignard reagents in the
presence of magnesium dibromide–diethyl ether or zinc dibromide
Magnesium bromide–diethyl ether (203 mg, 0.784 mmol) or
zinc dibromide (177 mg, 0.784 mmol) was added to a stirred
solution of the aldehyde 4 (0.784 mmol) in dry dichloro-
methane (5 ml) under nitrogen at Ϫ78 ЊC. After 40 minutes at
Ϫ78 ЊC, n-butylmagnesium chloride (0.43 ml of a 2.0 M solu-
tion in THF, 0.861 mmol) was added dropwise. After 3 hours at
Ϫ78 ЊC, saturated aqueous ammonium chloride (5 ml) was
added and the products were analysed and purified as described
above.
br m, OH), 3.02 (2H, m, CH2CH3), 2.14 (2H, td, J 6 and 1.5,
᎐
C᎐CCH ), 1.44 (2H, m, CH CH (CH ) CH ), 1.34 (3H, t, J 7,
᎐
2
2
2
2
3
3
NCH2CH3), 1.3–1.15 (6H, m, CH2CH2(CH2)3CH3), 0.90 (3H,
t, J 7, NCH2CH3), 0.80 (3H, t, J 7, (CH2)5CH3); δC(75 MHz,
CDCl3) 169.5, 135.2, 132.9, 132.6, 129.5, 129.1, 128.1, 126.9,
126.5, 125.5, 125.0, 87.6, 79.9, 63.8, 43.6, 39.0, 31.2, 28.5, 28.4,
22.4, 19.0, 14.0, 13.4 and 12.8; m/z (CI) 366 (1%, M ϩ Hϩ),
᎐
348 (18%, M Ϫ OH), 256 (2%, M Ϫ C᎐C(CH ) CH ) and
᎐
2
5
3
Additions of organolithiums to aldehyde 4d in the presence of
trimethylaluminium or DIBAL-H
74 (100%) (Found: M ϩ Hϩ, 366.2435. C24H31NO2 requires
M ϩ H, 366.2433).
Also obtained was (Ra*,1ЈS*)-N,N-diethyl-2-(1Ј-hydroxy-
non-2Ј-ynyl)-1-naphthamide syn-13c as a pale yellow oil, Rf 0.12
[2:1 petrol–EtOAc]; tR 9.1 [2:1 hexane–EtOAc]; νmax/cmϪ1
3426, 3058, 2955, 2931, 2870, 2858, 1610; δH(300 MHz, CDCl3)
7.89 (1H, d, J 8.5, ArH), 7.82 (1H, d, J 8.5, ArH), 7.78 (1H, m,
ArH), 7.62 (1H, m, ArH), 7.43 (2H, m, ArH), 5.53 (1H, t, J 2,
CHOH), 3.75 (1H, m, NCHAHBCH3), 3.60 (1H, m, NCHA-
Trimethylaluminium (20 µl of a 2 M solution in hexane) was
added to a stirred solution of the n-butyllithium (0.34 ml of
a 1.6 M solution in hexane) in THF (50 ml) under nitrogen
at Ϫ78 ЊC. The aldehyde 4d (112 mg, 0.4 mmol) was added
immediately and the mixture stirred for 1 hour at Ϫ78 ЊC, 2.5
hours at 0 ЊC, and 1 h at room temperature, poured into 1 M
HCl and extracted with dichloromethane (2 × 60 ml). The
extracts were washed with sodium bicarbonate solution and
with brine, dried (MgSO4) and evaporated under reduced pres-
sure. Analytical HPLC of the crude mixture showed a ratio of
93.8:6.2 of anti-12d:syn-12d. Purification by flash chromato-
graphy [4:1 petrol–EtOAc] gave the alcohols 12d (73 mg, 56%).
In a similar way, oct-1-ynyllithium (prepared as above from
n-butyllithium (0.26 ml of a 1.6 M solution in hexane) and
oct-1-yne (70 µl, 0.5 mmol) and trimethylaluminium (17 µl of a
2 M solution in hexane) gave a crude product containing (by
analytical HPLC) a mixture of 93:7 anti-13d:syn-13d. Purifi-
cation by flash chromatography [4:1 petrol–EtOAc] gave the
alcohol (75 mg, 66%) as a colourless oil.
HBCH3), 3.03 (1H, q, J 7, CHAHBCH3), 3.02 (1H, q, J 7.2,
᎐
NCH H CH ), 2.22 (2H, dt, J 7 and 2, C᎐CCH ), 1.46 (2H, m,
᎐
A
B
3
2
CH2CH2(CH2)3CH3), 1.34 (3H, t, J 7, NCH2CH3), 1.35–1.15
(6H, m, CH2CH2(CH2)3CH3), 0.91 (3H, t, J 7, NCH2CH3),
0.81 (3H, t, J 7, (CH2)5CH3); δC(75 MHz, CDCl3) 169.5, 135.9,
133.0, 132.2, 129.3, 128.9, 128.3, 127.1, 126.5, 124.8, 124.6,
88.0, 78.6, 62.7, 43.3, 39.2, 31.2, 28.5, 28.4, 22.5, 18.8, 14.0,
13.9 and 12.9; m/z (CI) 348 (9%, M Ϫ OH), 256 (2%, M Ϫ
᎐
C᎐C(CH ) CH ) and 74 (100%).
᎐
2
5
3
Also obtained was recovered aldehyde 4c (42 mg, 23%).
Similarly, with phenyllithium (1.8 M solution in cyclo-
hexane–ether), aldehyde 4c gave alcohols 14c; aldehyde 4d gave
alcohols 14d and aldehyde 4e gave alcohols 14e.
Similarly, with allylmagnesium bromide (1 M solution in
ether), aldehyde 4c gave alcohol 15c and aldehyde 4d gave
alcohols 15d.
In a similar way, oct-1-ynyllithium (prepared as above from
n-butyllithium (1 ml of a 1.6 M solution in hexane) and oct-1-
yne (0.23 ml, 1.6 mmol) and diisobutylaluminium hydride (1.6
ml of a 1 M solution in hexane) gave a crude product contain-
ing (by analytical HPLC) a mixture of >99:1 anti-13d:syn-13d.
Purification by flash chromatography [4:1 petrol–EtOAc] gave
the alcohol (75 mg, 50%) as a colourless oil.
Additions of methyltitanium trichloride
Titanium tetrachloride (1.13 ml, 1.13 mmol; 1 M solution in
1372
J. Chem. Soc., Perkin Trans. 1, 2000, 1363–1378

View Article Online
dichloromethane) was added to a stirred solution of methyl-
magnesium bromide (0.43 ml, 1.13 mmol; 3 M solution in
diethyl ether) or methyllithium (0.81 ml, 1.13 mmol, 1.4 M solu-
tion in diethyl ether) in THF (7.3 ml) at Ϫ78 ЊC under an
atmosphere of nitrogen. After 10 minutes, a solution of alde-
hyde 4 (240 mg, 0.64 mmol) in THF (5.9 ml) was added. The
mixture was allowed to warm to 0 ЊC and stirred for a further
2 hours. The mixture was poured into ice-cool aqueous 2 M
hydrochloric acid (15 ml) and diethyl ether (30 ml). Most of
the solvent was removed under reduced pressure without
external heating, and the aqueous residue was extracted with
dichloromethane (5 × 20 ml). The combined organic extracts
were dried (MgSO4), filtered and concentrated under reduced
pressure without external heating to give the crude product.
Analytical HPLC [2:1 hexane–EtOAc] gave the diastereo-
isomeric ratio (see Table 2), and the crude product was
purified by flash chromatography on silica gel [2:1 petrol–
EtOAc] to give the product alcohols in the yield shown in
Table 2.
In this way, the aldehyde 4c and MeMgBr gave the alcohols
11c along with (Ra*)-N,N-diethyl-2-((1R*,2R*)-2-{1-[(Ra*)-
(diethylamino)carbonyl]-2-naphthyl}-1,2-dihydroxyethyl)-1-
naphthamide 17 (R = Et) (59 mg, 12%) as a colourless oil, Rf
0.17 [1:1 petrol–EtOAc]; νmax/cmϪ1 3272, 3058, 2974, 2936,
2899, 2855, 2816, 2765, 1601; δH(300 MHz, CDCl3) 7.76 (2H,
m, ArH), 7.65 (2H, m, ArH), 7.51 (2H, d, J 8.5, ArH), 7.45 (4H,
m, ArH), 6.85 (2H, d, J 8.5, ArH), 6.01 (2H, s, CHOH), 5.21
(2H, s, CHOH), 3.92 (2H, m, 2 × NCHAHBCH3), 3.53 (2H,
m, 2 × NCHAHBCH3), 2.95 (4H, q, J 7.5, 2 × NCH2CH3),
1.39 (6H, t, J 7, 2 × CH2CH3), 0.90 (6H, t, J 7, 2 × CH2CH3);
δC(75 MHz, CDCl3) 171.6, 135.1, 132.7, 132.2, 128.3, 127.6,
126.8, 126.6, 126.2, 124.3, 74.1, 45.5, 43.7, 39.7, 14.0 and 13.0;
m/z (CI) 513 (4%, M ϩ Hϩ), 256 (4%, M Ϫ C16H18NO2) and 74
(100%) (Found: M ϩ Hϩ, 513.2754. C32H36N2O4 requires
M ϩ H, 513.2753).
3.69 (2H, m, CH2CH3), 1.32 (6H, t, J 7, 2 × CH3); δC(75 MHz,
CDCl3) 136.2, 134.6, 132.0, 128.0, 127.7, 127.4, 127.3, 126.8,
124.9, 123.3, 102.2, 62.6 and 15.2; m/z (EI) 308 (1%, Mϩ) and
49 (100%) (Found: Mϩ, 308.0410. C15H16O2Br requires M,
308.0412).
N,N-Dimethyl-2-(diethoxymethyl)-1-naphthamide 18a
A solution of the bromoacetal 19 in diethyl ether (15 ml) was
added dropwise over a period of 15 minutes to a solution of
tert-butyllithium (2.33 ml, 3.96 mmol; 1.7 M solution in pent-
ane) in diethyl ether (10 ml) at Ϫ78 ЊC under an atmosphere of
nitrogen. The resulting brown solution was stirred for 70 min-
utes. N,N-Dimethylcarbamoyl chloride (0.83 ml, 9.01 mmol)
was added in one portion and the mixture stirred for further 10
minutes, warmed to ambient temperature over a period of 60
minutes. Saturated aqueous sodium hydrogen carbonate (5 ml)
was added to the orange solution. The layers were separated
and the organic portion was washed with saturated aqueous
sodium hydrogen carbonate (20 ml) and brine (2 × 20 ml), dried
(MgSO4), filtered and concentrated under reduced pressure to
give a brown oil which was distilled (Kugelrohr, bp 243 ЊC, 0.5
mmHg) to afford the acetal 18a (353 mg, 47%) as a colour-
less oil, νmax(film)/cmϪ1 2974, 2932, 2874, 1629; δH(300 MHz,
CDCl3) 7.89 (2H, m, ArH), 7.80 (1H, d, J 8.7, ArH), 7.73 (1H,
m, ArH), 7.53 (2H, m, ArH), 5.67 (1H, s, CH(OEt)2), 3.88–3.52
(4H, m, 2 × CH2), 3.30 (3H, s, NCH3), 2.75 (3H, s, NCH3), 1.27
(6H, t, J 7.1, 2 × CH2CH3); δC(75 MHz, CDCl3) 169.8, 133.3,
133.2, 133.1, 129.0, 128.6, 128.1, 127.0, 126.5, 124.7, 123.5,
100.4, 62.8, 62.5, 38.3, 34.5, 15.1 and 15.0; m/z (CI) 256 (100%,
M Ϫ OEt); m/z (EI) 301 (7%, Mϩ), 256 (21%, M Ϫ OEt) and
127 (100%) (Found: Mϩ, 310.1673. C18H23NO3 requires M,
310.1678).
N-(tert-Butyl)-N-methyl-2-(diethoxymethyl)-1-naphthamide 18b
With MeLi, only 17 (R = Et) was obtained.
By the method given for 19, a mixture of the aldehyde 4b (206 g,
0.78 mmol), toluene-p-sulfonic acid monohydrate (15 mg, 0.08
mmol), 4 Å molecular sieves (ca. 0.5 g) and ethanol (10 ml) were
heated to reflux for 2 days. Purification by flash chromato-
graphy on neutral alumina [15:1 petrol–EtOAc] afforded the
acetal 18b (229 mg, 87%) as a white solid, Rf 0.38 [4:1 petrol
(bp 40–60 ЊC)–EtOAc]; mp 116–120 ЊC; νmax(film)/cmϪ1 3060,
2975, 2926, 2876, 1698, 1632; δH(300 MHz, CDCl3) 7.90–7.75
(4H, m, ArH), 7.58–7.48 (2H, m, ArH), 5.67 (1H, s, CH(OEt)2),
3.90 (1H, m, CHAHBCH3), 3.66 (2H, m, CH2CH3), 3.54 (1H,
m, CHAHBCH3), 2.72 (3H, s, NCH3), 1.72 (9H, s, t-Bu), 1.29
(3H, t, J 7, CH2CH3), 1.26 (3H, t, J 7, CH2CH3); δC(75 MHz,
CDCl3) 170.0, 135.6, 133.4, 132.2, 128.7, 128.2, 128.1, 126.8,
126.4, 124.6, 123.5, 100.3, 62.9, 62.7, 57.2, 33.8, 28.1, 15.2
and 15.1.
In the same way, the aldehyde 4d and MeMgBr gave the alco-
hols 11d along with (Ra*)-N,N-diisopropyl-2-((1R*,2R*)-
2-{1-[(Ra*)-(diisopropylamino)carbonyl]-2-naphthyl}-1,2-
dihydroxyethyl)-1-naphthamide 17 (R = i-Pr) (30 mg, 13%) as a
colourless oil, νmax/cmϪ1 3408, 3060, 3014, 2977, 2930, 2873,
2855; δH(300 MHz, CDCl3) 7.80–7.60 (4H, m, ArH), 7.50–7.30
(6H, m, ArH), 6.74 (2H, d, J 8.5, ArH), 5.97 (2H, d, J 4.5,
CHOH), 5.22 (2H, d, J 4.5, CHOH), 3.63 (2H, septet, J 7,
2 × NCH), 3.43 (2H, septet, J 6.5, 2 × NCH), 1.71 (12H, d, J 7,
4 × CH3), 1.03 (6H, d, J 6.5, 2 × CH3), 0.94 (6H, d, J 6.5,
2 × CH3); δC(75 MHz, CDCl3) 172.0, 134.9, 133.1, 132.6,
128.3, 128.2, 127.2, 126.5, 126.2, 126.2, 124.6, 74.9, 51.9, 46.7,
21.3, 20.8, 20.5 and 20.1; m/z (CI) 569 (27%, M ϩ Hϩ) and
284 (100%, M Ϫ C18H22NO2) (Found: M ϩ Hϩ, 569.3382.
C36H44N2O4 requires M ϩ H, 569.3379).
With MeLi, only 17 (R = i-Pr) was obtained.
N,N-Diethyl-2-(diethoxymethyl)-1-naphthamide 18c
In the same way, aldehyde 4c (1.329 g, 5.21 mmol), toluene-p-
sulfonic acid monohydrate (99 mg, 0.52 mmol), 4 Å molecular
sieves (ca. 1 g) and ethanol (20 ml) were heated to reflux for 24
hours. The crude product was purified by flash chromatography
on neutral alumina [4:1 petrol–EtOAc] and afforded the acetal
18c (875 mg, 51%) as a pale yellow oil, Rf 0.36 [4:1 petrol–
EtOAc]; νmax(film)/cmϪ1 2975, 2932, 2876, 1631; δH(300 MHz,
CDCl3) 8.0–7.7 (4H, m, ArH), 7.5 (2H, m, ArH), 5.56 (1H, s,
CH(OEt)2), 4.0–3.4 (6H, m, 3 × CH2), 3.2–3.0 (2H, m, CH2),
1.44 (3H, t, J 7, CH3), 1.28 (3H, t, J 7, CH3), 1.24 (3H, t, J 7,
CH3), 0.96 (3H, t, J 7, CH3); δC(75 MHz, CDCl3) 190.4, 168.8,
133.3, 133.0, 129.1, 128.7, 128.1, 126.7, 126.5, 125.1, 123.6,
100.5, 63.1, 62.5, 43.2, 38.8, 15.1, 15.1, 13.7 and 12.9; m/z
(CI) 330 (100%, M ϩ Hϩ) and 284 (0.3%, M Ϫ OEt); m/z (EI)
226 (14%, M Ϫ CH(OEt)2), 284 (31%, M Ϫ OEt), 300 (15%,
M Ϫ Et) and 183 (100%) (Found: M ϩ Hϩ 330.2060. C20H27-
NO3 requires M ϩ H, 330.2069).
1-Bromo-2-(diethoxymethyl)naphthalene 19
1-Bromo-2-formylnaphthamide
8 (1.155 g, 4.91 mmol),
toluene-p-sulfonic acid monohydrate (131 mg, 0.69 mmol), 4 Å
molecular sieves (ca. 1 g) and ethanol (15 ml) were heated to
reflux for 60 hours and cooled. 10% Aqueous sodium hydroxide
(15 ml) was added, the ethanol was removed under reduced
pressure, and diethyl ether (40 ml) was added. The layers were
separated and the organic portion was washed with 10% aque-
ous sodium hydroxide (2 × 15 ml), water (3 × 20 ml), dried
(MgSO4), filtered and concentrated under reduced pressure to
give an oil. Purification by flash chromatography on neutral
alumina [4:1 petrol–EtOAc] afforded the acetal 19 (634 mg,
42%) as a white solid, Rf 0.32 [80:1 petrol (bp 40–60 ЊC)–
EtOAc]; νmax(film)/cmϪ1 3061, 2976, 2926, 2896, 2878; δH(300
MHz, CDCl3) 8.42 (1H, J 8.5, ArH), 7.85 (3H, m, ArH), 7.61
(2H, m, ArH), 6.05 (1H, s, CH(OEt)2), 3.80 (2H, m, CH2CH3),
J. Chem. Soc., Perkin Trans. 1, 2000, 1363–1378
1373

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N,N-Diisopropyl-2-(diethoxymethyl)-1-naphthamide 18d
CHHcis), 4.89 (1H, dd, J 7.5 and 6.5, CHOH), 3.39 (1H, br m,
OH), 3.30 (3H, s, CH3), 2.76 (3H, s, CH3), 2.75 (1H, m, CH(OH)-
CHAHB), 2.62 (1H, m, CH(OH)CHAHB); δC(75 MHz, CDCl3)
170.5, 137.8, 134.5, 132.6, 132.3, 129.1, 128.9, 128.2, 127.1,
126.2, 124.4, 123.8, 117.7, 70.9, 40.9, 38.6 and 34.5; m/z (CI)
270 (92%, M ϩ Hϩ), 252 (37%, M Ϫ OH) and 242 (100%,
M Ϫ CH᎐CH ) (Found: C, 76.20; H, 6.85; N, 4.37%; M ϩ Hϩ,
In the same way, aldehyde 4d (1.120 g, 3.96 mmol), toluene-p-
sulfonic acid monohydrate (100 mg, 0.53 mmol), 4 Å molecular
sieves (ca. 1 g) and ethanol (25 ml) were heated to reflux for 3
days. The crude product was purified by flash chromatography
on neutral alumina [7:1 petrol–EtOAc] to give the acetal 18d
(834 mg, 59%) as a white solid, Rf 0.54 [4:1 petrol–EtOAc]; mp
135–141 ЊC; νmax(film)/cmϪ1 2975, 2931, 2897, 2874, 1629;
δH(300 MHz, CDCl3) 7.92–7.76 (4H, m, ArH), 7.56–7.50 (2H,
m, ArH), 5.56 (1H, s, CH(OEt)2), 4.08 (1H, dq, J 14 and 7,
OCHAHBCH3), 3.70–3.40 (5H, OCHAHBCH3, CH2, 2 × NCH),
1.81 (3H, d, J 7, NCHCH3), 1.73 (3H, d, J 7, NCHCH3), 1.32
(3H, t, J 7, OCH2CH3), 1.21 (3H, t, J 7, OCH2CH3), 1.13 (3H,
d, J 6.5, NCHCH3), 1.01 (3H, d, J 6.5, NCHCH3); δC(75 MHz,
CDCl3) 168.5, 134.3, 133.4, 132.6, 128.9, 128.5, 128.1, 126.5,
125.2, 123.9, 100.6, 65.8, 63.5, 62.3, 51.2, 46.2, 20.7, 20.5, 20.4,
20.3, 15.1 and 15.0; m/z (CI) 358 (6%, M ϩ Hϩ) and 312 (100%,
M Ϫ OEt); m/z (EI) 312 (5%, M Ϫ OEt) and 183 (100%)
(Found: C, 73.76; H, 8.66; N, 3.82%. C22H31NO3 requires C,
73.9; H, 8.7; N, 3.9%).
᎐
2
269.1415. C17H19NO2 requires C, 75.8; H, 7.1; N, 5.2%; M ϩ H,
269.1416).
The 1H NMR of the crude reaction mixture indicated traces
of 22, and samples of 15a in deuterochloroform lactonised
slowly on standing. For example, a solution of alcohols 15a (67
mg, 0.25 mmol) in deuterochloroform (0.6 ml) was allowed to
stand for 1 week at 60 ЊC. The solvent was removed under
reduced pressure to afford a brown oil which was purified by
flash chromatography on silica gel [4:1 petrol (bp 40–60 ЊC)–
EtOAc] to afford 3-allyl-1,3-dihydrobenzo[e]isobenzofuran-1-
one 22 (54 mg, 96%) as a colourless oil, Rf 0.27 [4:1 petrol–
EtOAc]; νmax(film)/cmϪ1 3073, 2917, 1749; δH(300 MHz, CDCl3)
9.06 (1H, d, J 8.4, ArH), 8.18 (1H, d, J 8.5, ArH), 8.02 (1H, d,
J 8, ArH), 7.78 (1H, m, ArH), 7.69 (1H, m, ArH), 7.56 (1H,
d, J 8.5, ArH), 5.84 (1H, ddt, J 17, 10.5 and 6.5, CH᎐CH ), 5.63
᎐
2
General procedure for the allylation of aldehydes with allyl-
trimethylsilane in the presence of SnCl4
(1H, t, J 5.5, ArCH(OCO)CH2CHCH2), 5.26 (1H, d, J 17.2,
CH᎐CHtransH), 5.19 (1H, d, J 10.5, CH᎐CHHcis), 2.90 (1H, m,
᎐
᎐
A solution of the aldehyde 4 (0.784 mmol) in dry dichloro-
methane (3 ml) was added dropwise to a solution of stannic
chloride (1.57 ml of a 1.0 M solution in dichloromethane,
1.568 mmol) under nitrogen at Ϫ78 ЊC. After 1 hour, allyl-
trimethylsilane (0.12 ml, 0.862 mmol) was then added in one
portion. After stirring at Ϫ78 ЊC for a further 2 hours the mix-
ture was allowed to warm to 0 ЊC, water (3 ml) was added, the
layers were separated, and the aqueous layer extracted with
dichloromethane (two 5 ml portions). The combined organic
fractions were washed with brine, dried (MgSO4), evaporated
under reduced pressure without external heating, analysed and
purified as described above.
CH H CH᎐CH ), 2.75 (1H, m, CH H CH᎐CH ); δ (75 MHz,
᎐
᎐
A
B
2
A
B
2
C
CDCl3) 170.5, 150.9, 135.3, 133.3, 131.2, 129.2, 128.9, 128.4,
127.2, 123.5, 120.4, 119.6, 118.5, 79.4 and 38.3; m/z (CI) 225
(100%, M ϩ Hϩ); m/z (EI) 224 (12%, Mϩ) and 183 (100%,
M Ϫ CH CH᎐CH ) (Found: Mϩ, 224.0838. C H O requires
᎐
2
2
15 12
2
M, 224.0837).
By the same methods, aldehyde 4b gave (Ra*,1ЈS*)-N-(tert-
butyl)-N-methyl-2-(1-hydroxybut-3-enyl)-1-naphthamide anti-
15b as a white solid, mp 103–107 ЊC; Rf 0.21 [1:1 petrol–
EtOAc]; tR 18.9 [8:1 hexane–EtOAc]; νmax(film)/cmϪ1 3398–
3262, 2977, 2960, 2916, 1614; δH(300 MHz, CDCl3) 7.86 (2H,
m, ArH), 7.75 (1H, m, ArH), 7.65 (1H, d, J 8.5, ArH), 7.58–
7.48 (2H, m, ArH), 5.86 (1H, ddt, J 17, 10.5 and 1, CH᎐CH ),
᎐
2
General procedure for allylation of aldehydes with allyltrimethyl-
silane in the presence of TiCl4
5.18 (1H, dd, J 17 and 1, CH᎐CHtransH), 5.10 (1H, dd, J 10.5
᎐
and 1, CH᎐CHHcis), 4.95 (1H, m, CHOH), 3.25 (1H, br s, OH),
᎐
Titanium tetrachloride (0.53 ml of a 1.0 M solution in dichloro-
methane, 0.530 mmol) was added in one portion to a stirring
solution of aldehyde 44 (0.265 mmol) in dry dichloromethane
(1.69 ml) under nitrogen at Ϫ78 ЊC. After 10 minutes, allyl-
trimethylsilane (0.1 ml, 0.636 mmol) was added dropwise to the
deep red solution over a 15 minute period and the mixture was
stirred for 3.5 hours at Ϫ78 ЊC. Saturated aqueous ammonium
chloride (2 ml) was added, the layers were separated, and the
aqueous layer extracted with dichloromethane (two 5 ml por-
tions). The combined organic fractions were washed with brine,
dried (MgSO4), evaporated under reduced pressure without
external heating, analysed and purified as described above.
By both of these methods, aldehyde 4a gave (Ra*,1ЈR*)-
N,N-dimethyl-2-(1Ј-hydroxybut-3Ј-enyl)-1-naphthamide anti-
15a, tR 8.8 min [1:1 hexane–EtOAc]; νmax(film)/cmϪ1 2972,
2933, 2844, 2736, 1702, 1619; δH(300 MHz, CDCl3) 7.88 (2H,
m, ArH), 7.67 (2H, m, ArH), 7.53 (2H, m, ArH), 5.91 (1H, ddt,
J 17, 10 and 6, CH᎐CH ), 5.24 (1H, d, J 17, CH᎐CHtransH), 5.21
2.84–2.70 (1H, m, CH H CH᎐CH ), 2.72 (3H, s, NCH ), 2.68–
᎐
A B 2 3
2.56 (1H, m, CH H CH᎐CH ), 1.69 (9H, s, t-Bu); δ (75 MHz,
᎐
A
B
2
C
CDCl3) 170.1, 137.4, 135.4, 135.3, 129.2, 128.8, 127.7, 126.7,
124.9, 124.3, 118.1, 71.3, 58.1, 41.2, 34.8 and 28.6; m/z (CI) 312
(43%, M ϩ Hϩ), 294 (100%, M Ϫ OH), 270 (27%, M Ϫ CH2-
CH᎐CH ) and 255 (36%, M Ϫ MeNt-Bu); m/z (EI) 311 (1%,
᎐
2
Mϩ) and 49 (100%) (Found: Mϩ, 311.1888. C20H25NO2 requires
M, 311.1885).
Also obtained was (Ra*,1ЈR*)-N-(tert-butyl)-N-methyl-2-
(1-hydroxybut-3-enyl)-1-naphthamide syn-15b as a white solid,
mp 139–141 ЊC; Rf 0.21 [1:1 petrol–EtOAc]; tR 36.2 [8:1
hexane–EtOAc]; νmax(film)/cmϪ1 3432–3415, 3058, 2977, 2960,
2923, 1615; δH(300 MHz, CDCl3) 7.88 (2H, m, ArH), 7.80 (1H,
m, ArH), 7.68 (1H, d, ArH), 7.59–7.49 (2H, m, ArH), 5.93 (1H,
m, CH CH᎐CH ), 5.32–5.21 (2H, m, CH᎐CH ), 4.92 (1H, dt,
᎐
᎐
2
2
2
J 9 and J 3.5, CHOH), 2.78 (3H, s, NCH3), 2.83–2.72 (1H, m,
CH H CH᎐CH ), 2.63 (1H, d, J 3.5, OH), 2.53 (1H, dt, J 14
᎐
A
B
2
and 8.5, CH H CH᎐CH ), 1.71 (9H, s, t-Bu); δ (75 MHz,
᎐
᎐
᎐
2
A
B
2
C
(1H, d, J 10, CH᎐CHHcis), 4.82 (1H, dd, J 9 and 4, CHOH),
CDCl3) 171.0, 136.8, 135.2, 134.5, 133.4, 129.5, 129.0, 128.7,
127.6, 126.6, 125.1, 124.3, 119.3, 71.7, 57.9, 44.0, 34.4 and 28.7;
m/z (CI) 312 (19%, M ϩ Hϩ), 294 (26%, M Ϫ OH), 270 (29%,
᎐
3.29 (3H, s, CH3), 2.78 (3H, s, CH3), 2.72 (1H, m, CHAHB-
CH᎐CH ), 2.55 (1H, m, CH H CH᎐CH ); δ (75 MHz, CDCl )
᎐
᎐
2
A
B
2
C
3
170.1, 137.1, 134.4, 132.7, 131.6, 129.1, 129.0, 128.1, 127.1,
126.2, 124.6, 123.7, 118.8, 71.0, 43.4, 38.3 and 34.6; m/z (CI)
270 (100%, M ϩ Hϩ) and 252 (17%, M Ϫ OH) (Found:
M ϩ Hϩ, 269.1412). C17H19NO2 requires M ϩ H, 269.1416).
Also obtained was (Ra*,1ЈS*)-N,N-dimethyl-2-(1Ј-hydroxy-
but-3Ј-enyl)-1-naphthamide syn-15a, tR 11.2 min [1:1 hexane–
EtOAc]; νmax(film)/cmϪ1 3377, 3061, 2975, 2929, 2851, 1614;
δH(300 MHz, CDCl3) 7.87 (2H, m, ArH), 7.63 (2H, m, ArH),
M Ϫ CH CH᎐CH ), 225 (42%, M Ϫ MeN-t-Bu) and 88
᎐
2 2
(100%); m/z (EI) 311 (1%, Mϩ) and 49 (100%) (Found: Mϩ,
311.1886. C20H25NO2 requires M, 311.1885).
By the same methods, aldehyde 4c gave the alcohols 15c and
aldehyde 4d gave the alcohols 15d.
General procedure for allylation of acetals with allyltrimethyl-
silane in the presence of TiCl4
7.54 (2H, m, ArH), 5.83 (1H, ddt, J 17, 10.5 and 7, CH᎐CH ),
᎐
2
5.15 (1H, dd, J 17 and 1.5, CH᎐CHtransH), 5.08 (1H, d, J 10.5,
Titanium tetrachloride (0.35 ml of a 1.0 M solution in dichloro-
᎐
1374
J. Chem. Soc., Perkin Trans. 1, 2000, 1363–1378

View Article Online
methane, 0.35 mmol) was added in one portion to a stirred
solution of acetal 18 (0.265 mmol) in dry dichloromethane (1.7
ml) under nitrogen at Ϫ78 ЊC. After 10 minutes, allyltrimethyl-
silane (0.1 ml, 0.64 mmol) was added dropwise over a 15 min
period to the deep red solution. The mixture was stirred for
3 hours at Ϫ78 ЊC. Saturated aqueous ammonium chloride (5
ml) was added, the layers were separated, and the aqueous layer
was extracted with dichloromethane (5 × 10 ml). The combined
organic fractions were washed with brine, dried (MgSO4),
evaporated under reduced pressure without external heating,
analysed and purified as described above.
(Found: M ϩ Hϩ, 340.2276. C22H29NO2 requires M ϩ H,
340.2276).
(Ra*,1ЈR*)- and (Ra*,1ЈS*)-N,N-Diethyl-2-(1Ј-ethoxybut-3Ј-
enyl)-1-naphthamide anti-21c and syn-21c. In the same way,
acetal 18c gave a crude product which was purified by flash
chromatography on silica gel [7:1 petrol–EtOAc] to give a mix-
ture of the two ethers 21c which were separated by preparative
HPLC [2:1 hexane–EtOAc] to afford anti-21c as a colourless
oil, Rf 0.47 [3:2 petrol–EtOAc]; tR 28.4 [16:1 hexane–EtOAc];
νmax(film)/cmϪ1 3058, 2975, 2934, 2895, 2873, 1632; δH(300
MHz, CDCl3) 7.88 (2H, m, ArH), 7.77 (1H, m, ArH), 7.70 (1H,
d, J 8.5, ArH), 7.52 (2H, m, ArH), 5.99 (1H, ddt, J 17, 10 and
6.5, CH᎐CH ), 5.14 (1H, d, J 17, CH᎐CHtransH), 5.07 (1H, d,
(Ra*,1ЈR*)- and (Ra*,1ЈS*)-N,N-Dimethyl-2-(1Ј-ethoxybut-
3Ј-enyl)-1-naphthamide anti-21a and syn-21a. By this method,
acetal 18a gave an inseparable (by flash chromatography
or HPLC) mixture of the ethers 21a. Purification by flash
chromatography on silica gel [2:1 petrol–EtOAc] afforded a
mixture of anti-21a and syn-21a as a colourless oil, Rf 0.31 [2:1
petrol–EtOAc]; νmax(film)/cmϪ1 3059, 3012, 2977, 2870, 2855,
1750, 1631; δH(300 MHz, CDCl3) anti-21a: 7.90 (2H, m, ArH),
7.68 (2H, m, ArH), 7.55 (2H, m, ArH), 5.99 (1H, ddt, J 17, 10
and 7, CH᎐CH ), 5.1 (2H, m, CH᎐CH ), 4.47 (1H, dd, J 8 and
᎐
᎐
2
J 10.2, CH᎐CHHcis), 4.49 (1H, dd, J 8.5 and 4, CHOEt), 3.96
᎐
(1H, m, CHAHBCH3), 3.60 (1H, m, CHAHBCH3), 3.43 (2H, m,
CH2CH3), 3.15 (2H, m, CH2CH3), 2.66 (1H, m, CHAHB-
CH᎐CH ), 2.54 (1H, m, CH H CH᎐CH ), 1.42 (3H, t, J 7,
᎐
᎐
2
A
B
2
CH3), 1.26 (3H, t, J 7, CH3), 1.00 (3H, t, J 7, CH3); δC(75 MHz,
CDCl3) 168.7, 136.6, 135.1, 132.7, 132.4, 129.4, 128.7, 128.0,
126.6, 126.0, 124.9, 123.4, 116.5, 79.1, 64.6, 42.8, 41.9, 38.4,
15.3, 14.0 and 12.7; m/z (CI) 326 (100%, M ϩ Hϩ) and 280
(22%, M Ϫ OEt); m/z (EI) 325 (3%, Mϩ) and 284 (100%,
᎐
᎐
2
2
5, CHOEt), 3.4 (2H, m, CH2CH3), 3.33 (3H, s, NCH3), 2.82
(3H, s, NCH ), 2.61 (2H, m, CH CH᎐CH ), 1.25 (3H, t, J 7.0,
M Ϫ CH CH᎐CH ) (Found: Mϩ, 325.2042. C21H27NO2
᎐
᎐
3
2
2
2
2
CH2CH3); syn-21a: 7.90 (2H, m, ArH), 7.68 (2H, m, ArH), 7.55
requires M, 325.2042).
(2H, m, ArH), 5.89 (1H, ddt, J 17, 10 and 6.5, CH᎐CH ), 5.1
Also obtained was syn-21c as a colourless oil, Rf 0.47 [3:2
petrol–EtOAc]; tR 34.6 [16:1 hexane–EtOAc]; νmax(film)/cmϪ1
3058, 2974, 2934, 2896, 2875, 1630; δH(300 MHz, CDCl3) 7.85
(2H, m, ArH), 7.74 (1H, m, ArH), 7.65 (1H, m, ArH), 7.50 (2H,
᎐
2
(2H, m, CH᎐CH ), 4.62 (1H, dd, J 8 and 5.5, CHOEt), 3.4 (2H,
᎐
2
m, CH2CH3), 3.31 (3H, s, NCH3), 2.77 (3H, s, NCH3), 2.71 (1H,
m, CH H CH᎐CH ), 2.44 (1H, m, CH H CH᎐CH ), 1.17 (3H,
᎐
᎐
A
B
2
A
B
2
t, J 7.0, CH2CH3); δC(75 MHz, CDCl3) 169.7, 169.6, 136.7,
136.5, 135.0, 133.1, 132.7, 129.1, 129.0, 128.8, 128.2, 128.1,
127.0, 127.0, 126.2, 126.1, 124.6, 124.5, 124.0, 123.5, 116.8,
116.6, 79.2, 77.9, 64.5, 64.2, 41.8, 41.7, 38.6, 38.1, 34.5, 34.4,
15.2 and 15.2; m/z (CI) 298 (86%, M ϩ Hϩ) and 242
m, ArH), 5.94 (1H, ddt, J 17.5, 10 and 7.5, CH᎐CH ), 5.08
᎐
2
(2H, m, CH᎐CH ), 4.56 (1H, dd, J 9 and 4, CHOEt), 4.00
᎐
2
(1H, m, CHAHBCH3), 3.50 (1H, m, CHAHBCH3), 3.39 (2H, m,
CH CH ), 3.07 (2H, m, CH CH ), 2.70 (1H, m, CH H CH᎐
᎐
2
3
2
3
A
B
CH ), 2.35 (1H, m, CH H CH᎐CH ), 1.38 (3H, t, J 7, CH ),
᎐
2
A
B
2
3
(100%); m/z (EI) 256 (M Ϫ CH CH᎐CH ) and 183 (31%)
1.11 (3H, t, J 7, CH3), 1.0 (3H, t, J 7, CH3); δC(75 MHz, CDCl3)
168.9, 136.1, 135.2, 133.4, 132.8, 128.8, 128.0, 126.6, 126.2,
125.1, 123.9, 116.6, 64.1, 43.0, 41.6, 38.4, 38.1, 15.1 and 13.8;
m/z (CI) 326 (100%, M ϩ Hϩ) and 280 (29%, M Ϫ OEt); m/z
᎐
2
2
(Found: M ϩ Hϩ, 298.1814. C19H23NO2 requires M ϩ H,
1
298.1807). Assignments in the H NMR spectrum were made
by COSY.
(EI) 325 (3%, Mϩ) and 284 (100%, M Ϫ CH CH᎐CH ) (Found:
᎐
2
2
(Ra*,1ЈR*)- and (Ra*,1ЈS*)-N-(tert-Butyl)-N-methyl-2-(1Ј-
ethoxybut-3Ј-enyl)-1-naphthamide anti-21b and syn-21b. In the
same way, acetal 18b gave a crude product which was purified
by flash chromatography on silica gel [7:1 petrol–EtOAc] to
give a mixture of the two ethers anti-21b and syn-21b as a white
solid. Preparative HPLC [16:1 hexane–EtOAc] gave anti-21b as
a sticky white solid, Rf 0.25 [7:1 petrol (bp 40–60 ЊC)–EtOAc];
tR 7.4 min [16:1 hexane–EtOAc]; νmax(film)/cmϪ1 3057, 2975,
2918, 2871, 1634; δH(300 MHz, CDCl3) 7.87 (2H, m, ArH), 7.76
(1H, m, ArH), 7.67 (1H, d, J 8.5, ArH), 7.53 (2H, m, ArH), 6.00
Mϩ, 325.2044. C21H27NO2 requires M, 325.2042).
(Ra*,1ЈR*)- and (Ra*,1ЈS*)-N,N-Diisopropyl-2-(1Ј-ethoxy-
but-3Ј-enyl)-1-naphthamide anti-21d and syn-21d. In the same
way, acetal 18d gave a crude product which was purified by flash
chromatography on silica gel [7:1 petrol–EtOAc] to yield a
mixture of the two naphthamides 21d. Preparative HPLC
[25:1 hexane–EtOAc] gave (Ra*,1ЈR*)-N,N-diisopropyl-2-(1Ј-
ethoxybut-3Ј-enyl)-1-naphthamide syn-21d as a white solid, mp
112–113 ЊC; νmax(film)/cmϪ1 3073, 3057, 2975, 2931, 2895, 2872,
1627; δH(300 MHz, CDCl3) 7.85 (3H, m, ArH), 7.71 (1H, d,
J 8.5, ArH), 7.51 (2H, m, ArH), 6.01 (1H, ddt, J 17, 10 and 6.5,
CH᎐CH ), 5.15 (1H, dd, J 17 and 2, CH᎐CHtransH), 5.07 (1H,
(1H, ddt, J 17, 10 and 7, CH᎐CH ), 5.14 (1H, dd, J 17 and 2,
᎐
2
CH᎐CHtransH), 5.07 (1H, d, J 10, CH᎐CHHcis), 4.55 (1H, dd,
᎐
᎐
J 9 and 4, CHOEt), 3.50–3.29 (2H, m, CH2CH3), 2.78 (3H, s,
᎐
᎐
2
NCH ), 2.68–2.48 (2H, m, CH CH᎐CH ), 1.70 (9H, s, t-Bu),
d, J 10, CH᎐CHHcis), 4.59 (1H, dd, J 9 and 3, CHOEt), 3.68
᎐
᎐
3
2
2
1.26 (3H, t, J 7, CH2CH3); δC(75 MHz, CDCl3) 170.0, 135.8,
135.3, 134.8, 132.8, 129.0, 128.3, 128.1, 126.9, 126.0, 124.4,
123.4, 116.4, 79.1, 64.5, 57.1, 41.9, 33.5, 28.1 and 15.2; m/z
(CI) 340 (100%, M ϩ Hϩ) and 294 (12%, M Ϫ OEt) (Found:
M ϩ Hϩ, 340.2275. C22H29NO2 requires M ϩ H, 340.2276).
Also obtained was syn-21b as a white solid, mp 105–107 ЊC;
Rf 0.25 [7:1 petrol–EtOAc]; tR 9.0 min [16:1 hexane–EtOAc];
νmax(film)/cmϪ1 2973, 2955, 2919, 2870, 2850, 1626; δH(300
MHz, CDCl3) 7.88 (2H, m, ArH), 7.74 (1H, m, ArH), 7.67 (1H,
d, J 8.5, ArH), 7.53 (2H, m, ArH), 5.93 (1H, ddt, J 17, 10 and
(2H, m, 2 × NCH), 3.50 (2H, q, J 7, CH2CH3), 1.81 (3H, d,
J 7, NCHCH3), 1.71 (3H, d, J 7, NCHCH3), 1.30 (3H, t, J 7,
CH2CH3), 1.17 (3H, d, J 6.5, NCHCH3), 1.05 (3H, d, J 6.5,
NCHCH3); δC(75 MHz, CDCl3) 168.5, 136.3, 135.4, 133.3,
132.7, 129.5, 128.2, 128.0, 126.4, 125.9, 124.9, 123.3, 116.4,
79.4, 64.5, 50.9, 46.1, 42.0, 21.2, 21.1, 20.6, 20.5 and 15.5;
m/z (CI) 354 (100%, M ϩ Hϩ) and 308 (15%, M Ϫ OEt); m/z
(EI) 353 (3%, Mϩ), 312 (32%, M Ϫ CH CH᎐CH ) and 270
᎐
2
2
(100%) (Found: Mϩ, 353.2346. C23H31NO2 requires M,
353.2355).
7.5, CH᎐CH ), 5.17–5.05 (2H, m, CH᎐CH ), 4.68 (1H, dd, J 8.5
Also obtained was (Ra*,1ЈR*)-N,N-diisopropyl-2-(1Ј-
ethoxybut-3Ј-enyl)-1-naphthamide anti-21d as a white solid, mp
125–128 ЊC; νmax(film)/cmϪ1 3084, 2977, 2959, 2926, 2871, 2856,
1625; δH(300 MHz, CDCl3) 7.86 (3H, m, ArH), 7.66 (1H, d,
J 8.5, ArH), 7.53 (2H, m, ArH), 6.10 (1H, ddt, J 17, 10.5 and
᎐
᎐
2
2
and 5, CHOEt), 3.41 (2H, m, CH2CH3), 2.72 (3H, s, NCH3),
2.70 (1H, m, CH H CH᎐CH ), 2.40 (1H, m, CH H CH᎐CH ),
᎐
᎐
A
B
2
A
B
2
1.70 (9H, s, t-Bu), 1.16 (3H, t, J 7, CH2CH3); δC(75 MHz,
CDCl3) 170.2, 135.5, 135.3, 132.8, 128.8, 128.4, 128.1, 126.9,
126.1, 124.5, 123.9, 116.6, 64.1, 57.3, 41.7, 34.1, 29.6, 28.0 and
15.1; m/z (CI) 340 (55%, M ϩ Hϩ) and 294 (100%, M Ϫ OEt)
6.5, CH᎐CH ), 5.18 (2H, m, CH᎐CH ), 4.61 (1H, dd, J 10.5
᎐
᎐
2
2
and 2, CHOEt), 3.63 (2H, septet, J 7, 2 × NCH), 3.43 (2H, m,
J. Chem. Soc., Perkin Trans. 1, 2000, 1363–1378 1375

View Article Online
CH2CH3), 2.82 (1H, m, CHAHBCH=CH2), 2.30 (1H, dd, J 14.5
and 6.5, CH H CH᎐CH ), 1.83 (3H, d, J 6.5, NCHCH ), 1.72
M ϩ Hϩ); m/z (EI) 296 (5%, Mϩ) and 196 (M Ϫ N(CH(CH3)2)2)
(Found: C, 77.14; H, 8.34; N, 9.42%. C19H24N2O requires C,
77.0; H, 8.1; N, 9.5%).
᎐
A
B
2
3
(3H, d, J 6.5, NCHCH3), 1.14 (6H, m, NCHCH3 and CH2CH3),
1.05 (3H, d, J 6.5, NCHCH3); δC(75 MHz, CDCl3) 168.7, 135.5,
134.4, 133.0, 129.1, 128.5, 128.0, 126.5, 126.2, 125.3, 124.0,
116.3, 76.8, 64.1, 50.8, 46.3, 41.3, 21.1, 20.9, 20.5, 20.3 and 15.1;
m/z (CI) 354 (100%, M ϩ Hϩ) and 308 (40%, M Ϫ OEt);
(Ra*,1ЈR*)- and (Ra*,1ЈS*)-N,N-Diisopropyl-2-[1Ј-(methyl-
amino)ethyl]-1-naphthamide anti-24 and syn-24
Methyllithium (0.48 ml, 0.77 mmol; 1.6 M solution in diethyl
ether) was added dropwise over 5 minutes to a solution of imine
23 (189 mg, 0.64 mmol) in THF (7 ml) at Ϫ78 ЊC under an
atmosphere of nitrogen. The resulting yellow solution was
stirred for 3 hours, saturated aqueous ammonium chloride (5
ml) was added and the mixture warmed to ambient temper-
ature. The THF was removed under reduced pressure without
external heating and the aqueous residue was extracted with
dichloromethane (5 × 10 ml). The combined organic extracts
were dried (MgSO4), filtered and concentrated under reduced
pressure at ambient temperature to give the crude product,
m/z (EI) 353 (3%, Mϩ), 312 (25%, M Ϫ CH CH᎐CH ) and
᎐
2
2
49/84/86 (100%) (Found: Mϩ, 353.2347. C23H31NO2 requires M,
353.2355).
Correlation of stereochemistry by ethylation of alcohols 15.
Method 1
Methyllithium (0.40 ml, 0.63 mmol; 1.6 M solution in diethyl
ether) and triethyloxonium tetrafluoroborate (144 mg, 0.76
mmol) were added to a solution of the alcohol syn-15a (170 mg,
0.63 mmol) in THF (8 ml) at Ϫ78 ЊC under an atmosphere of
nitrogen. After 10 min, the mixture was allowed to warm to
0 ЊC. After 20 minutes water (10 ml) was added to the white
suspension. The mixture was extracted with dichloromethane
(5 × 10 ml), and the combined organic extracts were dried
(MgSO4), filtered and concentrated under reduced pressure
without external heating to give the crude product. Purification
by flash column chromatography on silica gel [2:1 petrol (bp
40–60 ЊC)–EtOAc] afforded syn-21a (120 mg, 64%) as a colour-
less oil. Also obtained was lactone 22 (36 mg, 25%).
1
which contained (by H NMR) >96:4 syn-24:anti-24. Purifi-
cation by flash chromatography on silica gel [1:1 petrol–
EtOAc ϩ 1% triethylamine] gave syn-24 (183 mg, 92%) as a pale
brown solid. Recrystallisation from ethyl acetate afforded the
amine as pale brown rhombic prisms, mp 163–165 ЊC (EtOAc);
νmax(film)/cmϪ1 3316, 3052, 3009, 2968, 2934, 2899, 2873, 2799,
1617; δH(300 MHz, CDCl3) 7.87–7.80 (3H, m, ArH), 7.59 (1H,
d, J 8.7, ArH), 7.49 (2H, m, ArH), 3.96 (1H, q, J 6.5, ArCH-
(NHCH3)CH3), 3.63 (2H, m, 2 × NCH), 2.35 (3H, s, NCH3),
1.80 (3H, d, J 7, NCHCH3), 1.72 (3H, d, J 7, NCHCH3), 1.49
(3H, d, J 6.5, ArCH(NHCH3)CH3), 1.13 (3H, d, J 6.5,
NCHCH3), 1.03 (3H, d, J 7, NCHCH3); δC(75 MHz, CDCl3)
169.1, 137.6, 134.5, 132.6, 129.3, 128.4, 127.9, 126.4, 125.9,
125.1, 123.4, 55.6, 50.8, 46.1, 34.2, 21.2, 20.9, 20.8, 20.4 and
20.4; m/z (CI) 314 (100%, M ϩ Hϩ) (Found: C, 76.60; H, 9.04;
N, 9.13%. C20H28N2O requires C, 76.9; H, 9.0; N, 9.0%).
Heating syn-24 in CDCl3 for 5 days at 60 ЊC produced
enough anti-24 to allow identification of its NCH3 1H NMR
signal at δ 2.43 (3H, s).
Correlation of stereochemistry by ethylation of alcohols 15.
Method 2
Sodium hydride (16 mg, 2.05 mmol) was added to a solution of
the alcohol anti-15b (15 mg, 0.05 mmol) in DMF (2 ml) at 0 ЊC
under an atmosphere of nitrogen. After 30 minutes, ethyl iodide
(0.30 ml, 3.75 mmol) was added to the yellow solution. After
4 h, saturated aqueous ammonium chloride (5 ml) was added
and the mixture was extracted with dichloromethane (3 × 10
ml). The combined organic extracts were dried (MgSO4),
filtered and concentrated under reduced pressure without
external heating to give a crude product which was purified by
flash column chromatography on silica gel [7:1 petrol–EtOAc]
to yield anti-21b (15 mg, 94%) as a colourless oil.
By method 2, the alcohol syn-15c (31 mg, 0.10 mmol) in THF
(1.4 ml) gave, after 9 h, the ethyl ether syn-21c (30 mg, 89%) as a
colourless oil.
By method 2, the alcohol anti-15d (445 mg, 1.40 mmol)
gave, after 16 h, a crude product which was purified by flash
chromatography [3:1 petrol–EtOAc] to yield anti-21d (467 mg,
97%) as a white solid.
(Ra*,1ЈR*)- and (Ra*, 1ЈS*)-N,N-Diisopropyl-2-[1Ј-(methyl-
amino)pentyl]-1-naphthamide anti-25 and syn-25
In the same way, imine 23 (89 mg, 0.30 mmol) and n-butyl-
lithium (0.23 ml, 0.36 mmol; 1.6 M solution in hexanes) gave,
after 1 h, a crude product containing a ratio of 92:8 syn-
25:anti-25. Purification by flash chromatography on silica gel
[1:1 petrol–EtOAc ϩ 1% triethylamine] gave syn-25 (187 mg,
85%) as a pale brown solid, mp 110–111 ЊC; Rf 0.29 [1:1 petrol
(bp 40–60 ЊC)–EtOAc ϩ 1% triethylamine]; νmax(film)/cmϪ1
3326, 3057, 2961, 2933, 2872, 2859, 2797, 1624; δH(300 MHz,
CDCl3) 7.83 (3H, m, ArH), 7.54 (1H, d, J 8.8, ArH), 7.48 (2H,
m, ArH), 3.77 (1H, dd, J 8.5 and 4.5, CH(NHCH3)), 2.30 (3H,
s, NCH3), 1.90 (2H, m, CHAHBCHAHBCH2CH3), 1.80 (3H, d,
J 7, NCHCH3), 1.71 (3H, d, J 6.5, NCHCH3), 1.60 (1H, m,
CHAHB(CH2)2CH3), 1.36 (3H, m, CH2CHAHBCH2CH3), 1.12
(3H, d, J 6.5, NCHCH3), 1.02 (3H, d, J 6.5, NCHCH3),
0.94 (3H, t, J 7, (CH2)3CH3); δC(75 MHz, CDCl3) 169.1, 137.2,
134.8, 132.5, 129.4, 128.2, 127.9, 126.3, 125.9, 125.1, 123.8,
60.9, 50.9, 46.1, 35.1, 33.9, 29.6, 23.0, 21.0, 20.9, 20.5, 20.3 and
14.0; m/z (CI) 355 (100%, M ϩ Hϩ), 324 (1%, M Ϫ NHCH3)
and 254 (8%, M Ϫ NiPr2); m/z (EI) 354 (2%, Mϩ) and 196
(100%) (Found: Mϩ, 354.2677. C23H34N2O requires M,
354.2671).
Also obtained was 3-butyl-2-methyl-2,3-dihydro-1H-benzo[e]-
isoindol-1-one 28 (10 mg, 4%), Rf 0.60 [1:1 petrol–EtOAc ϩ
1% triethylamine]; νmax(film)/cmϪ1 3056, 2956, 2930, 2862,
1679; δH(300 MHz, CDCl3) 9.30 (1H, d, J 8.5, ArH), 8.01 (1H,
d, J 8.4, ArH), 7.94 (1H, d, J 8, ArH), 7.69 (1H, t, J 7.5, ArH),
7.58 (1H, t, J 7.5, ArH), 7.51 (1H, d, J 8.5, ArH), 4.47 (1H,
t, J 4.3, CH(CH2)3CH3), 3.19 (3H, s, NCH3), 2.09 (2H, m,
CHCH2CH2CH2CH3), 1.26 (2H, m, CH(CH2)2CH2CH3), 1.04
(1H, m, CHCHAHB(CH2)2CH3), 0.82 (3H, t, J 7.5, (CH2)3CH3),
N,N-Diisopropyl-2-(N-methylformimidoyl)-1-naphthamide 23
Aldehyde 4d28 (1.564 g, 5.23 mmol) was added to 40% aqueous
methylamine (15.7 g, 203 mmol) to form a white suspension
which clarified on heating on a steam bath for 60 minutes. The
solution was cooled to ambient temperature and the white pre-
cipitate isolated by filtration and dissolved in dichloromethane.
This solution was dried (MgSO4), filtered and concentrated
under reduced pressure to give a white solid which was
recrystallised from ethyl acetate to afford the imine 23 (1.308 g,
80%) as very fine white needles, mp 188–190 ЊC (ethyl acetate);
λmax/nm (εmax) (CH2Cl2) 254 (47080), 290 (11670); νmax(film)/
cmϪ1 3058, 3021, 2988, 2965, 2937, 2906, 2867, 2770, 1639,
1619; δ (300 MHz, CDCl ) 8.57 (1H, br m, CH᎐NCH ), 8.12
᎐
H
3
3
(1H, d, J 9, ArH), 7.94–7.82 (3H, m, ArH), 7.56 (2H, m, ArH),
3.67 (1H, septet, J 7, NCH), 3.59 (3H, d, J 1.5, CH᎐NCH ),
᎐
3
3.54 (1H, septet, J 6.5, NCH), 1.82 (3H, d, J 6.5, NCHCH3),
1.75 (3H, d, J 7, NCHCH3), 1.04 (3H, d, J 6.5, NCHCH3), 1.03
(3H, d, J 6.5, NCHCH3); δC(75 MHz, CDCl3) 168.3, 160.0,
137.5, 134.4, 129.3, 128.9, 128.2, 128.2, 127.4, 127.0, 125.3,
122.8, 51.3, 48.6, 46.4, 20.8, 20.6 and 20.4; m/z (CI) 297 (100%,
1376
J. Chem. Soc., Perkin Trans. 1, 2000, 1363–1378

View Article Online
0.76 (1H, m, CHAHB(CH2)2CH3); δC(75 MHz, CDCl3) 169.5,
145.3, 133.0, 131.9, 129.2, 127.9, 127.7, 126.6, 126.3, 123.9,
119.1, 61.0, 29.8, 27.0, 24.2, 22.5 and 13.8; m/z (CI) 254 (100%,
M ϩ Hϩ) and 196 (4%, M Ϫ C4H9); m/z (EI) 253 (14%, Mϩ),
196 (100%, M Ϫ C4H9) (Found: Mϩ, 253.1472. C17H19NO
requires M, 253.1467).
Heating syn-25 in CDCl3 for 5 days at 60 ЊC produced
enough anti-25 to allow identification of its NCH3 1H NMR
signal at δ 2.40 (3H, s).
chromatography on silica gel [15:1 petrol–EtOAc ϩ 1% tri-
ethylamine] to afford (Ra*,1ЈS*)-N,N-diisopropyl-2-{1-[benzyl-
(methyl)amino]pentyl}-1-naphthamide syn-27 (51 mg, 16%) as
a sticky pale yellow solid, Rf 0.18 [4:1 petrol (bp 40–60 ЊC)–
EtOAc ϩ 1% triethylamine]; tR 3.0 min [15:1 hexane–
EtOAc ϩ 1% triethylamine]; νmax(film)/cmϪ1 3059, 3026, 2960,
2934, 2870, 2858, 2792, 1709, 1630; δH(300 MHz, CDCl3) 7.80–
7.70 (3H, m, ArH), 7.52 (1H, d, J 8.5, ArH), 7.42–7.34 (2H, m,
ArH), 7.25–7.06 (5H, m, ArH), 3.87 (1H, dd, J 9.5 and 4.5,
CHN), 3.60 (1H, d, J 13.5, PhCHAHB), 3.6–3.4 (2H, m,
2 × NCH), 3.43 (1H, d, J 13.5, PhCHAHB), 2.06 (3H, s, NCH3),
2.1 (1H, m, CHAHB(CH2)2CH3), 1.71 (3H, d, J 6.9, NCHCH3),
1.7 (1H, m, CH2CHAHBCH2CH3), 1.6 (1H, m, CHAHB-
(CH2)2CH3), 1.58 (3H, d, J 7, NCHCH3), 1.5–1.2 (3H, m,
CH2CHAHBCH2CH3), 1.05 (3H, d, J 6.6, NCHCH3), 0.90–0.84
(6H, m, NCHCH3 and (CH2)3CH3); δC(75 MHz, CDCl3) 169.2,
135.0, 134.8, 132.5, 129.8, 128.5, 128.4, 127.9, 127.8, 127.3,
126.3, 126.0, 125.9, 125.6, 125.5, 64.9, 58.3, 50.7, 46.2, 37.8,
33.4, 29.1, 23.1, 21.1, 21.1, 20.7, 20.4 and 14.1; m/z (CI) 445
(100%, M ϩ Hϩ); m/z (EI) 387 (6%, M Ϫ C4H9), 353 (2%,
M Ϫ CH2Ph) and 49 (100%) (Found: M ϩ Hϩ, 445.3223.
C30H46N2O requires M ϩ H, 445.3219).
Also obtained was 3-benzyl-3-butyl-2-methyl-2,3-dihydro-1H-
benzo[e]isoindol-1-one 30 (134 mg, 54%) as a pale yellow solid,
Rf 0.17 [4:1 petrol–EtOAc ϩ 1% triethylamine]; νmax(film)/
cmϪ1 3061, 3030, 2955, 2930, 2861, 1679; δH(300 MHz, CDCl3)
9.18 (1H, dd, J 8 and 1, ArH), 8.01 (1H, d, J 8, ArH), 7.91 (1H,
d, J 7.5, ArH), 7.66–7.52 (2H, m, ArH), 7.44 (1H, d, J 8.5,
ArH), 7.03 (3H, m, ArH), 6.77 (2H, m, ArH), 3.34 (1H, d, J 14,
CHAHBPh), 3.18 (1H, d, J 14, CHAHBPh), 3.17 (3H, s, NCH3),
2.16 (2H, m, CH2(CH2)2CH3), 1.22 (2H, m, (CH2)2CH2CH3),
0.84 (1H, m, CH2CHAHBCH2CH3), 0.77 (3H, t, J 7.3,
(CH2)3CH3), 0.49 (1H, m, CH2CHAHBCH2CH3); δC(75 MHz,
CDCl3) 169.4, 147.5, 134.8, 132.9, 131.7, 129.5, 129.0, 127.9,
127.8, 127.6, 126.7, 126.6, 126.2, 124.1, 118.9, 68.2, 43.4,
35.7, 24.8, 24.7, 22.4 and 13.8; m/z (CI) 344 (100%, M ϩ Hϩ)
and 252 (6%, M Ϫ CH2Ph); m/z (EI) 252 (100%,
M Ϫ CH2Ph) (Found: M ϩ Hϩ, 344.2017. C24H25NO requires
M ϩ H, 344.2014).
(Ra*,1ЈR*)- and (Ra*,1ЈS*)-N,N-Diisopropyl-2-{1-[benzyl-
(methyl)amino]ethyl}-1-naphthamide anti-26 and syn-26
Methyllithium (0.52 ml, 0.83 mmol; 1.6 M solution in diethyl
ether) was added dropwise over 5 minutes to a solution of imine
23 (204 mg, 0.69 mmol) in THF (7 ml) at Ϫ78 ЊC under an
atmosphere of nitrogen. After 3 hours benzyl bromide (0.13 ml,
1.10 mmol) was added and after a further 5 minutes the mix-
ture was warmed to 0 ЊC. After 30 minutes saturated aqueous
ammonium chloride (5 ml) was added and the solvent was
removed under reduced pressure without external heating. The
aqueous residue was extracted with dichloromethane (5 × 10
ml) and the combined organic extracts were dried (MgSO4),
filtered and concentrated under reduced pressure to give the
crude product which contained (by analytical HPLC (10:1
hexane–EtOAc ϩ 1% triethylamine)) a ratio of 96:4 syn-
26:anti-26. Purification by flash chromatography on silica gel
[15:1 petrol–EtOAc ϩ 1% triethylamine] afforded syn-26 (41
mg, 15%) as a colourless oil that solidified on standing, Rf 0.26
[4:1 petrol (bp 40–60 ЊC)–EtOAc ϩ 1% triethylamine]; tR 5.2
min [10:1 hexane–EtOAc ϩ 1% triethylamine]; νmax(film)/cmϪ1
3059, 3027, 2975, 2933, 2873, 2837, 2790, 1629; δH(300 MHz,
CDCl3) 7.80–7.66 (4H, m, ArH), 7.42–7.34 (2H, m, ArH), 7.20
(5H, m, ArH), 3.65–3.46 (4H, m, 2 × NCH, CHAHBPh and
CH(CH3)N), 3.17 (1H, d, J 13.7, CHAHBPh), 2.08 (3H, s,
NCH3), 1.71 (3H, d, J 6.9, NCHCH3), 1.63 (3H, d, J 6.7,
NCHCH3), 1.42 (3H, d, J 6.5, CH3CHN), 1.07 (3H, d, J 6.5,
NCHCH3), 0.93 (3H, d, J 6.5, NCHCH3); δC(75 MHz, CDCl3)
169.0, 140.5, 138.4, 133.7, 132.7, 129.4, 128.7, 128.3, 127.9,
127.9, 126.3, 125.9, 125.2, 124.6, 60.7, 59.6, 50.6, 46.2, 39.4,
22.0, 21.3, 20.9, 20.5 and 20.4; m/z (CI) 403 (10%, M ϩ Hϩ) and
302 (100%, M Ϫ N(CH(CH3)2)2); m/z (EI) 210 (100%) and 91
(49%, CH2Ph) (Found: M ϩ Hϩ, 403.2756. C27H34N2O requires
M ϩ H, 403.2749).
Heating syn-27 in CDCl3 for 5 days at 60 ЊC produced
enough anti-27 to allow identification of its NCH3 1H NMR
signal at δ 2.22 (3H, s) and to assign its retention time as tR 3.0
min [15:1 hexane–EtOAc ϩ 1% triethylamine].
Also obtained was 3-benzyl-2,3-dimethyl-2,3-dihydro-1H-
benzo[e]isoindol-1-one 29 (133 mg, 54%) as a pale yellow solid,
Crystal data for anti-15c†
Rf 0.11 [4:1 petrol–EtOAc ϩ 1% triethylamine]; λmax/nm (εmax
)
Single crystals of anti-15c were grown from ethyl acetate,
mounted on a thin glass fibre and transferred to the cold gas
stream of the diffractometer. C19H23NO2, M = 297.38, mono-
clinic, a = 10.1424(14), b = 16.7857(13), c = 10.7011(15) Å,
β = 114.446(9)Њ, U = 1658.5(4) Å3, T = 123(1) K, space group
P21/c (no. 14), Z = 4, Dc = 1.191 g cmϪ3, µ(Mo-Kα) = 0.077
mmϪ1. Data collected on a Rigaku AFC7R diffractometer,
4038 reflections measured, θmax = 26.99Њ, 3609 reflections
unique (Rint = 0.0108).50 Final agreement factors for 227
parameters gave R1 = 0.0562, wR2 = 0.1036 and GOF =
1.010 based on all 3609 data, final difference map ϩ0.28 and
(CH2Cl2) 236 (45640), 300 (7623); νmax/cmϪ1 3060, 3029, 2968,
2929, 1678; δH(300 MHz, CDCl3) 9.04 (1H, d, J 7.7, ArH),
7.88 (1H, d, J 8.5, ArH), 7.79 (1H, d, J 8, ArH), 7.51 (1H,
m, ArH), 7.43 (1H, m, ArH), 7.32 (1H, d, J 8.5, ArH), 6.96–
6.88 (3H, m, ArH), 6.70–6.64 (2H, m, ArH), 3.22 (1H, d,
J 14, CHAHBPh), 3.08 (3H, s, NCH3), 3.05 (1H, d, J 14, CHA-
HBPh), 1.54 (3H, s, CH3); δC(75 MHz, CDCl3) 168.7, 149.2,
135.1, 132.9, 131.7, 129.4, 129.1, 127.8, 127.7, 126.7, 126.3,
125.6, 124.1, 118.9, 64.9, 43.3, 24.6 and 23.9; m/z (CI) 301
(100%, M ϩ Hϩ) and 210 (8%, M Ϫ CH2Ph); m/z (EI) 210
(100%, M Ϫ CH2Ph) (Found: M ϩ Hϩ, 302.1545. C21H19NO
requires M ϩ H, 302.1545).
Ϫ0.24 e ÅϪ3 51
.
Heating syn-26 in CDCl3 for 5 days at 60 ЊC produced
enough anti-26 to allow identification of its NCH3 1H NMR
signal at δ 2.24 (3H, s) and to assign its retention time as tR
[10:1 hexane–EtOAc ϩ 1% triethylamine] 4.3 min.
Crystal data for anti-15d†
Single crystals of anti-15d were grown from ethyl acetate,
mounted on a thin glass fibre and transferred to the cold gas
stream of the diffractometer. C21H27NO2, M = 325.44, mono-
clinic, a = 11.4254(4), b = 20.1558(6), c = 16.4936(5) Å, β =
99.506(1)Њ, U = 3746.1(2) Å3, T = 123(1) K, space group P21/c
(Ra*,1ЈR*)- and (Ra*,1ЈS*)-N,N-Diisopropyl-2-{1Ј-[benzyl-
(methyl)amino]pentyl}-1-naphthamide anti-27 and syn-27
(no. 14), Z = 8, Dc = 1.154 g cmϪ3, µ(Mo-Kα) = 0.073 mmϪ1
.
In the same way, imine 23, n-butyllithium (0.55 ml, 0.88 mmol;
1.6 M solution in hexanes) and benzyl bromide (0.13 ml, 1.10
mmol) gave a crude product containing a ratio of 92:8 syn-
27:anti-27 (by analytical HPLC) which was purified by flash
† CCDCreferencenumber207/413.Seehttp://www.rsc.org/suppdata/p1/
b0/b000669f for crystallographic files in .cif format.
J. Chem. Soc., Perkin Trans. 1, 2000, 1363–1378
1377

View Article Online
Z. A. Starikova, A. I. Yanovsky, Y. N. Belokon’ and H. Hopf,
Tetrahedron: Asymmetry, 1996, 7, 3445.
24 C. Baldoli, P. Del Buttero, D. Perdicchia and T. Pilati, Tetrahedron,
1999, 55, 14089.
25 G. Delogu, L. de Lucchi and P. Maglioli, Synlett, 1989, 28.
26 V. Snieckus, Chem. Rev., 1990, 90, 879.
Data collected on a Bruker AXS SMART CCD diffracto-
meter, 31581 reflections measured, data truncated to 0.80 Å
(θmax 26.37Њ, 99.8% complete), 7639 reflections unique
(Rint = 0.0441).50 Final agreement factors for 501 parameters
gave R1 = 0.0490, wR2 = 0.1078 and GOF = 1.007 based on all
7639 data, final difference map ϩ0.37 and Ϫ0.22 e ÅϪ3 51
.
27 For further examples of organolithium additions to naphthalene
rings, see references 2 and 28. See also J. Clayden, N. Westlund and
F. X. Wilson, Tetrahedron Lett., 1999, 40, 7883; J. Clayden, C. S.
Frampton, C. McCarthy and N. Westlund, Tetrahedron, 1999, 55,
14161; S. Thayumanavan, P. Beak and D. P. Curran, Tetrahedron
Lett., 1996, 37, 2899; A. Ahmed, J. Clayden and M. Rowley,
Chem. Commun., 1998, 297; A. I. Meyers, G. P. Roth, D. Hoyer,
B. A. Barner and D. Laucher, J. Am. Chem. Soc., 1988, 110, 4611;
M. Shimano and A. I. Meyers, J. Am. Chem. Soc., 1994, 116, 6437;
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M. Shimano and A. I. Meyers, J. Org. Chem., 1996, 61, 5714; B.
James and A. I. Meyers, Tetrahedron Lett., 1998, 39, 5301; T. G.
Gant and A. I. Meyers, Tetrahedron, 1994, 50, 2297; A. I. Meyers,
J. D. Brown and D. Laucher, Tetrahedron Lett., 1987, 28, 5283 and
B. Plunian, J. Mortier, M. Vaultier and L. Toupet, J. Org. Chem.,
1996, 61, 5206.
Crystal data for syn-24†
Single crystals of syn-24 were grown from ethyl acetate,
mounted on a thin glass fibre and transferred to the cold gas
stream of the diffractometer. C20H28N2O, M = 312.44, ortho-
rhombic, a = 16.219(3), b = 11.966(3), c = 18.823(3) Å, U =
3653(1) Å3, T = 123(1) K, space group Pbca (no. 61), Z = 8,
Dc = 1.136 g cmϪ3, µ(Mo-Kα) = 0.070 mmϪ1. Data collected on
a Bruker AXS SMART CCD diffractometer, 19092 reflections
measured, data truncated to 0.80 Å (θmax 26.37Њ, 99.5% com-
plete), 3715 reflections unique (Rint = 0.0238).50 Final agreement
factors for 218 parameters gave R1 = 0.0473, wR2 = 0.1014 and
GOF = 1.000 based on all 4011 data, absolute structure not
28 A. Ahmed, R. A. Bragg, J. Clayden, L. W. Lai, C. McCarthy,
J. H. Pink, N. Westlund and S. A. Yasin, Tetrahedron, 1998, 54,
13277.
determined, final difference map ϩ0.25 and Ϫ0.22 e ÅϪ3 51
.
29 J. G. Smith, P. W. Dibble and R. E. Sandborn, J. Org. Chem., 1986,
3762.
30 H. B. Hass and M. L. Bender, Org. Syn., 1963, Coll. Vol. 4, 932.
31 B. M. Trost and G.-j. Liu, J. Org. Chem., 1981, 46, 4617.
32 G. D. Hartman, W. Halczenko and B. T. Phillips, J. Org. Chem.,
1985, 50, 2427.
33 For a similar discussion see references 22 and 24, and H. Gruza,
K. Kiciak, A. Krasi´nski and J. Jurczak, Tetrahedron: Asymmetry,
1997, 8, 2627.
Acknowledgements
We are grateful to the EPSRC, Roche Discovery (Welwyn) and
Zeneca for CASE awards (to N. W. and C. McC.), to the Royal
Society for an Equipment Grant, and to Dr Francis Wilson for
helpful discussions.
34 T. Ooi, N. Kagoshima, H. Ichikawa and K. Maruoka, J. Am. Chem.
Soc., 1999, 121, 3328.
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1378
J. Chem. Soc., Perkin Trans. 1, 2000, 1363–1378