Generation of ketone dilithio α,β-dianions and their reactions with electrophiles

Article abstract of DOI:10.1016/j.tet.2005.01.047

Ketone dilithio α,β- and α,β′-dianions can be generated by a tin-lithium exchange reaction of the lithium enolate of β-tributyltin substituted ketones. A chelation-aided approach, which employs β-dichlorobutyltin substituted ketones and n-BuLi, is also us

Full text of DOI:10.1016/j.tet.2005.01.047

Tetrahedron 61 (2005) 3383–3392
Generation of ketone dilithio a,b-dianions and their reactions
with electrophiles
Hiroyuki Nakahira,a Masanobu Ikebe,a Yoshiaki Oku,a Noboru Sonoda,a Takahide Fukuyamab
and Ilhyong Ryub,
*
aDepartment of Applied Chemistry, Graduate School of Engineering, Osaka University, Suita, Osaka 565–0871, Japan
bDepartment of Chemistry, Faculty of Arts and Sciences, Osaka Prefecture University, Sakai, Osaka 599–8531, Japan
Received 5 October 2004; revised 8 November 2004; accepted 6 January 2005
Abstract—Ketone dilithio a,b- and a,b0-dianions can be generated by a tin–lithium exchange reaction of the lithium enolate of b-tributyltin
substituted ketones. A chelation-aided approach, which employs b-dichlorobutyltin substituted ketones and n-BuLi, is also useful for the
generation of ketone a,b-dianions having the Z-geometry at the alkene. The generated dianions can be transformed into substituted ketones
by reaction with various carbon electrophiles.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
One of the distinct advantages of carbanion chemistry1 over
radical and cation chemistry is the relatively facile
generation and control of carbon species having doubly
reactive centers.2 We have been interested in the behavior of
dianionic species of ketones, and in particular lithium
enolate species containing an additional carbon–lithium
center. Initial work on ketone dianion chemistry involving
the generation and reactions of ketone a,a0- and a,a-dianion
species were reported by Harris3 and Kowalski4 and their
co-workers, respectively. In terms of ketone a,b0-dianions,
the Goswami group reported a-diethylphosphoryl dianionic
species A,5 in which the cationic counterions were sodium
and lithium. Subsequently, the Cohen group reported the
synthesis of ketone a,b-dianions.8,9 In the reactions of these
ketone a,b-dianions with alkyl halides, two anionic centers
are available for reaction. We found that the dianions
exhibited higher reactivity at the allylic lithium moiety
rather than lithium enolate moiety toward a variety of
carbon electrophiles.10 In this article, we would like to
report on the full scope of the generation of ketone a,b-
dianions using tin–lithium exchange reactions and their
reactions with electrophilic reagents.
first dilithio species of a,b0-dianionic species B, character-
istically bearing a cyclopropyllithium moiety.6
Stimulated by this earlier work, we became interested in the
preparation and reaction of the simple dilithio species C.
Thus, we previously reported a two-step method for its
generation from b-tributylstannyl ketones via conversion to
the corresponding lithium enolates and subsequent tin–
lithium exchange reactions.7 Very recently we also reported
a one-step method, starting from b-dichlorobutylstannyl
ketones and using 4 equiv of BuLi, which was found to be
particularly useful for the regio- and stereo-controlled
2. Results and discussion
2.1. Generation of ketone a,b-dianions from b-tributyl-
stannyl ketones
Keywords: Dianion; Electrophiles; Enolate; Tin–lithium exchange reaction;
Z geometry.
* Corresponding author. Tel.:C81 6 879 7401; fax: C81 6 879 7402;
e-mail: ryu@ms.cias.osakafu-u.ac.jp
In order to generate ketone dilithio a,b-dianions, we
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.01.047

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H. Nakahira et al. / Tetrahedron 61 (2005) 3383–3392
Scheme 1.
initially attempted a two-step method using b-tributylstan-
nyl ketones 1 as the substrates. The b-tributylstannyl
ketones 1, were conveniently prepared by the chemoselec-
tive alkylation at the Sn atom of the corresponding b-tri-
chlorostannyl ketones, readily available from the ring
opening reaction of siloxycyclopropanes with tin tetra-
chloride11 or hydrotrichlorostannylation of enones,12 using
3 equiv of n-BuMgBr. Treatment of tert-butyl b-(tributyl-
stannyl)ethyl ketone (1a) with lithium diisopropylamide
(LDA) in THF at K78 8C gave the corresponding lithium
enolate 2a having a Z geometry selectively. The resulting
lithium enolate was then treated with n-BuLi at K78 to 0 8C
for 30 min to give the expected lithium ketone dilithio
a,b-dianion 3a, which was trapped as its silyl ether 4a
(Scheme 1).
along with the silylated products of the unreacted enolates
(2b, trace; 2b0, 35%; and 2b00, 16%). These results
suggested that (i) Li–Sn exchange proceeds in a stereo-
specific manner, (ii) the ease of Li–Sn exchange decreases
in the order: 2b (allyl-Z)O2b00 (homoallyl)[2b0 (allyl-E),
and (iii) the inefficient Li–Sn exchange of E-enolate 2b0
may be due to the lack of stabilization by internal
coordination of the lithioxy group on the resulting lithium
dianionic species.
Although the use of LDA gave a mixture of enolates in the
above case, lithium hexamethyldisilazide (LHMDS), a
bulkier base, was able to generate Z-allyl anion 2b from
1b selectively, which then underwent a selective conversion
to dianion 3b (Scheme 3).
Table 1 summarizes examples of the present two-step
procedure for the generation of ketone dianions 3 from 1.
Thus, 1c–f were smoothly converted into the correspond-
ing Z-allyl dianions (runs 1–4). On the other hand, the
reactions of 1g–i, underwent H-abstractions of the less
hindered C–H bonds generating dianions 3g–i having
homoallyllithium structures (runs 5–7). Consistent with
the observation in the experiment of 2b00 in Scheme 2, the
Sn-Li exchange reaction required a prolonged reaction
time (3 h at K78 to 0 8C).
To determine the ease of the tin–lithium exchange reaction,
we examined the reaction of stereo- and regioisomeric
mixtures of lithium enolates derived from isopropyl b-
tributylstannyl ketone 1b (Scheme 2). Deprotonation of 1b
by LDA gave a mixture of three isomeric lithium enolates,
2b (allyl-Z, 30%), 2b0 (allyl-E, 39%), and 2b00 (homoallyl,
26%). Li–Sn exchange reactions of this mixture of the
enolates with n-butyllithum at K78 to 0 8C for 30 min,
followed by TMSCl trapping, gave bis-silylated products 3b
(allyl-Z, 29%), 3b0 (allyl-E, trace), and 3b00 (homoallyl, 7%)
Scheme 2. Tin–Li exchange of lithium enolates derived from 1b.

H. Nakahira et al. / Tetrahedron 61 (2005) 3383–3392
3385
Scheme 3.
Table 1. Generation of dianions 3 from b-tributylstannyl ketones 1a
Run
1
Substrate 1
Conditionsb
A
Dianions 3
Silylated product 4
Yield(%)c
70
(E/ZZ0/100)
3c
3d
3e
4c
4d
4e
1c
1d
1e
2
3
B
B
79
(E/ZZ0/100)
85
(E/ZZ0/100)
4
A
75d
3f
4f
1f
5
6
C
C
72 (95)e
76 (98)e
3g
1g
4g
1h
4h
3h
3i
7
C
72 (99)e
1i
4i
a Carried out on 1 mmol scale in THF (5 mL),for details, see Section 4.
b Conditions A: LDA, K78 8C, 2 h/K78 to 0 8C, 30 min. Conditions B: LHMDS, K78 8C, 5 h/K78 to 0 8C, 30 min. Conditions C: LDA, K78 8C, 15 min/
K78 to 0 8C, 3 h.
c Isolated by flash chromatography.
d GC yield.
e Regioisomeric purity (%).
We also attempted the Michael addition reaction of Bu3SnLi
with enones to generate lithium enolates of b-tributylstannyl
ketones (Scheme 4). Treatment of 5 with tributyltinlithium
in THF at K78 8C for 30 min, followed by addition of
n-butyllithium (1.2 equiv, K78 to 0 8C, 30 min), gave the
expected dianion 6, which was transformed to silyl ether 7
(Scheme 4). Thus, with these two methods, it is possible to
prepare regioisomers 6 and 3i, respectively. Dianion 3f was
also generated from 8 by this Michael addition/Sn-Li
exchange protocol.
2.2. Regio- and stereocontrolled generation of dianions
from coordinated b-butyldichlorostannyl ketones
It seems likely that the a-protons of b-trichloro- or b-
butyl(dichloro)stannyl ketones are more acidic than those of

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H. Nakahira et al. / Tetrahedron 61 (2005) 3383–3392
Scheme 4. Michael addition route to ketone a,b-dianions.
b-tributylstannyl ketones due to the intramolecular coordi-
nation and/or the inductive effect of the chlorostannyl
group.12 Seeking a convenient approach for stereo- and
regioselective dianion formation, we became interested in
the utility of such coordinated species. As outlined in
Scheme 5, in principle the reaction of b-halostannyl ketones
with organolithium reagents can proceed through three
different pathways: a, substitution at Sn; b, addition to the
carbonyl; and c, abstraction of the a and/or a0-proton.
Although the chelation-free substrate, 1a, undergoes
exclusive nucleophilic attack on the carbonyl group in the
presence of n-BuLi, we envisioned that in the case of a
coordinated species, a-deprotonation to form a Z enolate
would be more rapid than nucleophilic attack on the
carbonyl, which would permit a straightforward method for
the generation of ketone dianions.
10a. This side-reaction involves dehydrostannylation to
give tert-butyl vinyl ketone, followed by the Michael
addition of n-BuLi.
Consequently, we found that the selective generation of the
desired dianion could be achieved using b-dichlorobutyl-
stannyl ketones as substrates, with which no such side-
reaction was observed. For example, when 11a was treated
with n-BuLi (4 equiv) in THF at K78 to 0 8C for 30 min, a
clean reaction took place to give the desired dianion 3a,
which was transformed to the disilylated product 4a in 90%
yield by trapping with TMSCl (Scheme 7). Treatment of
11a with 3 equiv of n-BuLi at K78 8C and then subsequent
quenching with TMSCl at that temperature gave the Z-enol
silyl ether 12 of the corresponding b-tributylstannyl ketone
in 72% yield, supporting the intermediacy of 2a as a
precursor to the dianion 3a. Thus abstraction of an a-proton
by n-BuLi precedes the second alkylation at the Sn atom.
With this working hypothesis, we initially examined the
reaction of b-trichlorostannyl ketone 9a with n-BuLi
(5.5 equiv) in THF, followed by trapping with TMSCl
(Scheme 6). The reaction did indeed give bis-silylated
product 4a via silylation of the expected ketone a,b-dianion
3a in 44%, together with the formation of enol silyl ether
Results of this ‘one operation’ method are also summarized
in Table 2. In each case dianion formation was conducted by
simply adding 4 equiv of n-BuLi to a THF solution of b-
dichlorobutylstannyl ketone 11 at K78 8C and warming up
Scheme 5. Possible reaction courses for the reaction of b-Sn ketones with BuLi.
Scheme 6.

H. Nakahira et al. / Tetrahedron 61 (2005) 3383–3392
3387
Scheme 7. Generation of dianion 3a from b-dichlorobutylstannyl ketone 11a and n-BuLi.
Table 2. Generation of ketone a,b-dianions from b-dichlorobutylstannyl ketonesa
Run
1
Substrate
Dianions
Product
Yield (%)b
90 (E/ZZ0/100)
84 (E/ZZ0/100)
78 (E/ZZ0/100)
4a
4b
11a
11b
3a
3b
2
3
3c
3e
11c
4c
4
5
81 (E/ZZ0/100)
76 (E/ZZ0/100)
4e
11e
4j
3j
11j
a Carried out on 1 mmol scale in THF (5 mL), for details, see Section 4.
b Isolated by flash chromatography.
to 0 8C and the regio- and the stereochemical outcomes of
the dianion 3 were confirmed by derivatization to 4. It is
noteworthy that the deprotonation of substrates 11b and 11e
with a-methylene and a0-methine groups occurred with high
a-regio- and Z-stereoselectivity. Although the regioselec-
tive deprotonation of substrates having two methylene
groups a and a0 to the carbonyl is particularly difficult to
achieve, it is significant that the a-selective deprotonation
was achieved with 11j. It should be noted that this ‘one
operation’ route has an advantage over the b-tributylstannyl
ketone route, vide supra, since it is amine-free, which allows
for a clean transmetallation.9
straightforward access to lithium enolates 13 having a Z-
geometry (Scheme 8).
2.3. Reactions of ketone a,b-dianions with carbon
electrophiles
Scheme 8. Dianions 3 as a precursor for (Z)-form enolates.
As outlined in Scheme 8, the alkylation of dianions 3 with
alkyl bromides took place more rapidly at the b-position
than at the a-position under controlled conditions, allowing
If alkylation of dilithio species 3 were to occur at the
carbonyl b-position preferentially, this would provide

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H. Nakahira et al. / Tetrahedron 61 (2005) 3383–3392
Table 3. Reactions of ketone a,b-dianions 3 with electrophilesa
Run
1
Dianionsb
Electrophiles (equiv) conditions
Product
Yield (%)c
1) n-C5H11Br (3)
K78 to K20 8C, 1 h
2) H2O
71
3a
3a
14
15
1) CH2]CHCH2Br (3)
K78 8C, 15 min
2) H2O
2
62
CH2ZCHCH2Br (5)d
K78 to K20 8C, 1 h
3
4
3a
3a
74
16
17
1) n-C5H11Br (3)
K78 to K20 8C, 1 h
2) Me3SiCl (2)
70e
K78 8C, 15 min
1) CH2ZCH(CH2)4Br (3)
K78 to K20 8C, 1 h
2) Me3SiCl (2)
5
6
3a
3a
69e
K78 8C, 15 min
18
1) n-C5H11Br (2)
K78 to K20 8C, 1 h
2) CH2]CHCH2Br (3)d
K78 to K25 8C, 1 h
70
19
20
1) Me2C]CHCH2Br (3)
K78 8C, 15 min
2) H2O
7
53
3b
3b
1) EtO(CH2)2Br (3)
K78 to K20 8C, 1 h
2) Me3SiCl (2)
8
72e
68e
68e
81e
K78 8C, 15 min
21
22
1) n-C5H11Br (3)
K78 to K20 8C, 1 h
2) Me3SiCl (2)
9
3b
K78 8C, 15 min
1) BrCH2CH(Me)CH2Cl (3)
K78 to K20 8C, 1 h
2) Me3SiCl (2)
10
3e
K78 8C, 15 min
23
24
1) n-C8H17Br (3)
K78 to K20 8C, 1 h
2) Me3SiCl (2)
11
3e
K78 8C, 15 min
a Carried out on 1 mmol scale in THF(5 mL), for details, see Section 4.
b Generated from b-tributylstannyl ketones.
c Isolated by flash chromatography.
d HMPA (0.5 mL) was added.
e E/ZZ0/100.

H. Nakahira et al. / Tetrahedron 61 (2005) 3383–3392
3389
the conversion to Z lithium enolates 13. Table 3 summarizes
the results of the reactions of dianions 3 with electrophiles.
For example, treatment of 3a with n-pentyl bromide
(3 equiv) at K78 to K20 8C for 1 h followed by proton
quenching gave the b-alkylated ketone 14 in 71% yield (run
1). Similarly, b-allylated ketone 15 was prepared by the
treatment with allyl bromide (K78 8C, 15 min) followed by
proton quenching in 62% yield (run 2). The use of excesses
of allyl bromide and HMPA as a co-solvent led to the
formation of diallylated product 16 in 74% yield, which
could be useful as a substrate for Grubbs’ ring closing olefin
metathesis leading to cyclohexene derivatives.13 Needless
to say, the b-alkylated enolates can undergo a number of
useful transformations developed for metal enolates.14
Treatment with TMSCl after b-alkylation of 3 provided b-
alkylated enol silyl ethers having Z geometry in good yields
(runs 4, 5, 8, 9, 10 and 11), which are important compounds
in synthesis.15 The b-alkylation/a-allylation sequence lead-
ing to 19 was also successful (run 6).
under an atmosphere of argon. Tetrahydrofuran (THF) was
dried by distillation from sodium/benzophenone ketyl prior
to use. Diisopropylamine, 1,1,1,3,3,3-hexamethyldisilazane
(HMDS), and other reagents were distilled prior to use. b-
Tributylstannyl ketones, b-dichlorobutylstannyl ketones,
and b-trichlorostannyl ketones were prepared by reported
procedure.9,10 For column chromatography, silica gel 60
(230–400 mesh ASTM, E. Merck) was used. GLC analysis
was carried out with a Shimadzu GC-12A apparatus using
Hicap-CBP-M25-025 (OV-1 type) column. 1H NMR
spectra were recorded on a JEOL JNM-GSX-270
(270 MHz), a JEOL JNM-GSX-400 (400 MHz), or Bruker
AM 600 (600 MHz) spectrometer in CDCl3. 13C NMR
spectra were recorded on a JEOL JNM-GSX-270 (68 MHz)
spectrometer in CDCl3. IR spectra were obtained from a
Perkin–Elmer 1610 FTIR spectrometer. Mass spectra
(EIMS) and high-resolution mass spectra (HRMS) were
recorded on JEOL JMS-DX303 HF spectrometer using
electronical ionization (EI) mass spectrometry. Elemental
analyses were performed by the Analytical Center, Faculty
of Engineering, Osaka University.
The reaction of dianion 3a with valeraldehyde 25 followed
by proton quenching gave 47% of the desired homoaldol
product 26 (Scheme 9).16 However, optimization of the
yields seems rather difficult, because of the large number of
byproducts presumably resulting from competing rapid
aldol reactions. Interestingly, however, a small amount of
1,2-diol 27 was isolated as a byproduct, which demonstrates
the ambident character of the ketone a,b-dianions.17
4.2. General procedure for the generation of ketone
dilithio a,b-dianions 3 from b-tributylstannyl ketones 1
and then trapping with TMSCl
The preparation of (Z)-4,4-dimethyl-3-(trimethylsiloxy)-1-
(trimethylsilyl)-2-pentene (4a) is described as a typical
example. tert-Butyl (b-tributylstannyl)ethyl ketone 1a
(0.432 g, 1.0 mmol) was added to a cooled solution
(K78 8C) of LDA (prepared from diisopropylamine
(0.184 mL, 1.3 mmol) and n-BuLi (1.58 M hexane solution,
0.76 mL, 1.2 mmol)) in THF (5 mL). After stirring for 2 h at
K78 8C, n-BuLi (1.58 mL, 2.5 mmol) was added slowly.
The reaction mixture was allowed to warm to 0 8C and
stirred for 30 min. After cooling to K78 8C, the mixture was
quenched with Me3SiCl (0.271 g, 3.0 mmol). The quenched
mixture was diluted with water and extracted with ether.
The ether layers were combined, washed with brine, dried
with MgSO4, filtered, and concentrated under reduced
pressure. The crude material was purified by flash
chromatography (SiO2) using pentane as eluent to yield
(Z)-4,4-dimethyl-3-(trimethylsiloxy)-1-(trimethylsilyl)-2-
pentene (4a) (0.235 g, 91%). For 4d and 4e, HMDS was
used instead of diisopropylamine. The spectral data of b-
silyl enol silyl ether 4a–i are as follows.
Scheme 9.
3. Conclusions
In summary, we have shown that ketone a,b- and a,b0-
dianions can be generated by a Sn-Li exchange reaction of
the lithium enolate of b-tributyltin substituted ketones using
n-BuLi. A chelation-aided approach, which employs b-
dichlorobutyltin substituted ketones and n-BuLi, was
particularly useful for the straightforward generation of
ketone a,b-dianions having Z/allyl-type structures. The thus
generated dianions can be transformed into ketones by
sequential reaction at the b and a positions with a variety of
carbon electrophiles.
4.2.1. (Z)-4,4-Dimethyl-3-(trimethylsiloxy)-1-(trimethyl-
silyl)-2-pentene (4a). A colorless oil. H NMR (270 MHz,
1
CDCl3) d K0.02 (s, 9H), 0.22 (s, 9H), 1.03 (s, 9H), 1.29 (d,
JZ8.2 Hz, 2H), 4.51 (t, JZ8.2 Hz, 1H). 13C NMR
(68 MHz, CDCl3) d K1.79, 1.19, 15.68, 28.73, 36.31,
98.81, 157.02. IR (NaCl) 1656 cmK1 (C]C). MS (EI) 258
(MC). Anal. Calcd for C13H30OSi2: C, 60.37; H, 11.71.
Found: C, 60.36; H, 11.71.
4.2.2. (Z)-4-Methyl-3-(trimethylsiloxy)-1-(trimethyl-
silyl)-2-pentene (4b).
A
colorless oil. 1H NMR
4. Experimental
(270 MHz, CDCl3) d K0.01 (s, 9H), 0.19 (s, 9H), 1.02 (d,
JZ6.7 Hz, 6H), 1.31 (d, JZ8.6 Hz, 2H), 2.16 (m, 1H), 4.43
(dt, JZ0.6, 8.6 Hz, 1H). 13C NMR (68 MHz, CDCl3) d
K1.69, 0.86, 14.99, 21.04, 34.49, 100.24, 154.72. IR (NaCl)
1664 cmK1 (C]C). MS (EI) 244 (MC). HRMS calcd for
4.1. General remarks
All reactions were carried out in oven-dried glassware and

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H. Nakahira et al. / Tetrahedron 61 (2005) 3383–3392
C12H28OSi2 244.1678, found 244.1694. Anal. Calcd for
C12H28OSi2: C, 58.92; H, 11.56. Found: C, 58.55; H, 11.51.
1.43–1.78 (m, 5H), 1.94–2.05 (m, 2H), 2.32–2.36 (m, 1H),
4.85 (t, JZ7.0 Hz, 1H). 13C NMR (68 MHz, CDCl3) d
K0.86, 0.40, 18.99, 24.05, 26.08, 28.03, 31.85, 41.03,
106.24, 159.48. IR (NaCl) 1658 cmK1 (C]C). MS (EI) 270
(MC).
4.2.3. (Z)-1-Phenyl-1-(trimethylsiloxy)-3-(trimethyl-
silyl)-1-propene (4c).
A
colorless oil. 1H NMR
(270 MHz, CDCl3) d 0.04 (s, 9H), 0.13 (s, 9H), 1.57 (d,
JZ8.2 Hz, 2H), 5.26 (t, JZ8.2 Hz, 1H), 7.19–7.45 (m, 5H).
13C NMR (68 MHz, CDCl3) d K1.48, 0.77, 16.89, 107.29,
125.11, 126.82, 127.95, 139.67, 147.91. IR (NaCl)
1638 cmK1 (C]C). MS (EI) 278 (MC). Anal. Calcd for
C15H26OSi2: C, 64.66; H, 9.42. Found: C, 64.47; H, 9.65.
4.3. Generation of ketone dilithio a,b-dianions 3 from
a,b-unsaturated ketones via Michael addition of
Bu3SnLi
The preparation of 1-(trimethylsiloxy)-2-(trimethylsilyl-
methyl)-1-cycloheptene (7) is described as a typical
example. 2-Methylenecycloheptanone (0.124 g, 1.0 mmol)
was added to a cooled solution (K78 8C) of Bu3SnLi
(prepared from Bu3SnH (0.466 g, 1.6 mmol) and LDA
(1.2 mmol)) in THF (5 mL). After stirring for 30 min at
K78 8C, n-BuLi (1.5 M hexane solution, 1.67 mL,
2.5 mmol) was added. The reaction mixture was allowed
to warm to 0 8C and stirred for 30 min. After re-cooling to
K78 8C, the mixture was quenched with Me3SiCl (0.271 g,
3.0 mmol). The quenched mixture was diluted with water
and extracted with ether. The ether layers were combined,
washed with brine, dried with MgSO4, filtered, and
concentrated under reduced pressure. The crude material
was purified by flash chromatography (SiO2) using pentane
as eluent to yield 1-(trimethylsiloxy)-2-(trimethylsilyl-
methyl)-1-cycloheptene (7) (0.176 g, 65%).
4.2.4. (Z)-1-Cyclopropyl-1-(trimethylsiloxy)-3-(tri-
methylsilyl)-1-propene (4d). A colorless oil. 1H NMR
(270 MHz, CDCl3) d K0.02 (s, 9H), 0.20 (s, 9H), 0.45–0.57
(m, 4H), 1.26–1.35 (m, 1H), 1.31 (d, JZ7.9 Hz, 2H), 4.41 (t,
JZ7.9 Hz, 1H). 13C NMR (68 MHz, CDCl3) d K1.66, 0.97,
5.48, 14.98, 15.81, 101.17, 150.08. IR (NaCl) 1664 cmK1
(C]C). MS (EI) 242 (MC). HRMS calcd for C12H26OSi2
242.1522, found 242.1548.
4.2.5. (Z)-4-Methyl-3-(trimethylsiloxy)-1-(trimethyl-
silyl)-2-hexene (4e). A colorless oil. H NMR (270 MHz,
1
CDCl3) d K0.01 (s, 9H), 0.19 (s, 9H), 0.86 (t, JZ7.4 Hz,
3H), 1.00 (d, JZ6.7 Hz, 3H), 1.18–1.37 (m, 1H), 1.32 (d,
JZ8.0 Hz, 2H), 1.40–1.58 (m, 1H), 1.87–2.03 (m, 1H), 4.41
(t, JZ8.0 Hz, 1H). 13C NMR (68 MHz, CDCl3) d K1.64,
0.97, 11.68, 15.19, 18.48, 27.42, 41.66, 101.43, 153.05. IR
(NaCl) 1663 cmK1 (C]C). MS (EI) 258 (MC). HRMS
calcd for C13H30OSi2 258.1835, found 258.1898.
4.3.1. 1-(Trimethylsiloxy)-2-(trimethylsilylmethyl)-1-
cycloheptene (7). A colorless oil. 1H NMR (270 MHz,
CDCl3) d 0.00 (s, 9H), 0.16 (s, 9H), 1.43 (s, 2H), 1.46–1.58
(m, 4H), 1.60–1.74 (m, 2H), 1.98 (t, JZ5.4 Hz, 2H), 2.26 (t,
JZ5.3 Hz, 2H). 13C NMR (68 MHz, CDCl3) d K0.64, 0.95,
23.48, 25.73, 26.91, 31.81, 33.40, 34.99, 117.74, 145.82. IR
(NaCl) 1655 cmK1 (C]C). MS (EI) 270 (MC). Anal. Calcd
forC14H30OSi2:C,62.16;H,11.18.Found:C,61.90;H, 11.24.
4.2.6. 2-(Trimethylsiloxy)-3-(trimethylsilylmethyl)bicy-
clo[2.2.1]hept-2-ene (4f). A colorless oil. 1H NMR
(270 MHz, CDCl3) d 0.01 (s, 9H), 0.19 (s, 9H), 1.07–1.64
(m, 8H), 2.51 (s, 1H), 2.58 (s, 1H). 13C NMR (68 MHz,
CDCl3) d K0.98, 0.64, 14.27, 26.21, 26.26, 45.29, 45.39,
45.61, 118.04, 150.22. IR (NaCl) 1656 cmK1 (C]C). MS
(EI) 268 (MC). HRMS calcd for C14H28OSi2 268.1678,
found 268.1679.
4.4. General procedure for the generation of ketone
dilithio a,b-dianions 3 from b-dichlorobutylstannyl
ketones 11 and the trapping with TMSCl
4.2.7. 2-(Trimethylsiloxy)-4-(trimethylsilyl)-1-butene
(4g). A colorless oil. 1H NMR (270 MHz, CDCl3) d
K0.01 (s, 9H), 0.19 (s, 9H), 0.61–0.70 (m, 2H), 1.93–2.02
(m, 2H), 4.00 (s, 1H), 4.07 (s, 1H). 13C NMR (68 MHz,
CDCl3) d K1.81, 0.12, 13.99, 30.72, 88.63, 161.90. IR
(NaCl) 1635 cmK1 (C]C). MS (EI) 216 (MC). HRMS
calcd for C10H24OSi2 216.1365, found 216.1376.
(Z)-3-(Trimethylsiloxy)-1-(trimethylsilyl)-2-nonene (4j) is
described as a typical example. A solution of b-dichloro-
butylstannyl ketone 11j (0.365 g, 0.94 mmol) in THF
(10 mL) was treated with n-BuLi (1.66 M hexane solution,
2.40 mL, 3.95 mmol) at K78 8C. The reaction mixture was
allowed to warm to 0 8C and stirred for 30 min. After
cooling to K78 8C, the mixture was quenched with Me3SiCl
(0.253 g, 2.35 mmol). The quenched mixture was diluted
with water and extracted with ether. The ether layers were
combined, washed with brine, dried with MgSO4, filtered,
and concentrated under reduced pressure. The crude
material was purified by flash chromatography (SiO2)
using pentane as eluent to yield (Z)-3-(trimethylsiloxy)-1-
(trimethylsilyl)-2-nonene (4j) (0.204 g, 76%). Regio-
isometic purity, O99% (GC analysis of the crude products).
4.2.8. 1-(Trimethylsiloxy)-6-(trimethylsilylmethyl)-1-
cyclohexene (4h). A colorless oil. 1H NMR (270 MHz,
CDCl3) d 0.01 (s, 9H), 0.17 (s, 9H), 0.43 (dd, JZ10.7,
15.0 Hz, 1H), 0.38–0.47 (m, 1H), 1.06 (dd, JZ3.3, 15.0 Hz,
1H), 1.18–1.52 (m, 2H), 1.74–1.99 (m, 1H), 1.89–2.03 (m,
2H), 2.04–2.17 (m, 1H), 4.75 (t, JZ3.7 Hz, 1H). 13C NMR
(68 MHz, CDCl3) d K0.71, 0.37, 19.96, 20.28, 24.22,
31.29, 35.05, 102.88, 154.91. IR (NaCl) 1711 cmK1
(C]C). MS (EI) 256 (MC). HRMS calcd for C13H28OSi2
256.1678, found 256.1672.
4.4.1.
(Z)-3-(Trimethylsiloxy)-1-(trimethylsilyl)-2-
1
nonene (4j). A colorless oil. H NMR (270 MHz, CDCl3)
d K0.01 (s, 9H), 0.17 (s, 9H), 0.85–0.90 (m, 3H), 1.22–1.33
(m, 8H), 1.35–1.48 (m, 2H), 1.99 (t, JZ7.3 Hz, 2H), 4.41 (t,
JZ8.0 Hz, 1H). 13C NMR (68 MHz, CDCl3) d K1.63, 0.81,
14.07, 14.96, 22.67, 27.24, 28.83, 31.73, 36.60, 103.11,
4.2.9. 1-(Trimethylsiloxy)-6-(trimethylsilylmethyl)-1-
cycloheptene (4i). A colorless oil. H NMR (270 MHz,
CDCl3) d 0.02 (s, 9H), 0.17 (s, 9H), 0.67 (dd, JZ8.8,
14.6 Hz, 1H), 0.89 (m, 1H), 0.96 (dd, JZ6.1, 14.6 Hz, 1H),
1

H. Nakahira et al. / Tetrahedron 61 (2005) 3383–3392
3391
149.02. IR (NaCl) 1669 cmK1 (C]C). MS (EI) 286 (MC).
Anal. Calcd for C15H34OSi2: C, 62.84; H, 11.97. Found: C,
62.89; H, 12.16.
0.21 (S, 9H), 1.03 (s, 9H), 1.25–1.43 (m, 6H), 1.88–2.10 (m,
4H), 4.49 (t, JZ6.8 Hz, 1H), 4.90–5.02 (m, 2H), 5.73–5.88
(m, 1H). 13C NMR (68 MHz, CDCl3) d 1.05, 26.16, 28.62,
28.82, 28.96, 29.83, 33.75, 36.18, 104.15, 114.11, 139.17,
158.01. IR (NaCl) 1660 cmK1 (C]C). MS (EI) 268 (MC).
HRMS calcd for C16H32OSi 268.2222, found 268.2241.
Anal. Calcd for C16H32OSi: C, 71.54; H, 12.03. Found: C,
71.75; H, 12.14.
4.5. General procedure for the bond formation at the b-
position of ketone dilithio a,b-dianions 3 with alkyl
bromides
The preparation of 2,2-dimethyl-3-decanone (14) is
described as a typical example. b-Tributylstannyl ketone
1a (0.403 g, 1.0 mmol) was added to a cooled solution of
LDA (prepared from diisopropyl amine (0.184 mL,
1.3 mmol) and n-BuLi (1.58 M hexane solution, 0.76 mL,
1.2 mmol)) in THF (5 mL). After stirring for 2 h at K78 8C,
n-BuLi (1.58 M hexane solution, 1.58 mL, 2.5 mmol) was
added. The reaction mixture was allowed to warm to 0 8C
and stirred for 30 min. After re-cooling to K78 8C, n-pentyl
bromide (0.453 g, 3.0 mmol) was added. The mixture was
allowed to warm to K20 8C and stirred for 1 h. Dilution
with ether followed by washing with water, concentration,
and flash chromatography (SiO2, 10% ether in pentane)
gave 2,2-dimethyl-3-decanone (14) (0.130 g, 71%).
4.5.6. 2,8-Dimethyl-7-nonen-3-one (20). A colorless oil.
1H NMR (270 MHz, CDCl3) d 1.06 (d, JZ7.0 Hz, 6H), 1.57
(s, 3H), 1.58 (m, 2H), 1.67 (s, 3H), 1.96 (m, 2H), 2.41 (t, JZ
7.3 Hz, 2H), 2.57 (m, 1H), 5.06 (t, JZ7.0 Hz, 1H). 13C
NMR (68 MHz, CDCl3) d 17.74, 18.32, 23.95, 25.74, 27.52,
39.79, 40.85, 123.95, 132.26, 214.93. IR (NaCl) 1674 cmK1
(C]C), 1712 cmK1 (C]O). MS (EI) 168 (MC). HRMS
calcd for C11H20O 168.1514, found 168.1517.
4.5.7. (Z)-2-Methyl-7-ethoxy-3-(trimethylsiloxy)-3-hep-
tene (21). A colorless oil. H NMR (270 MHz, CDCl3) d
1
0.00 (s, 9H), 1.02 (d, JZ6.8 Hz, 6H), 1.19 (t, JZ8.5 Hz,
3H), 1.23–1.45 (m, 2H), 1.99–2.05 (m, 2H), 2.11–2.17 (m,
1H), 3.40 (t, JZ6.8 Hz, 2H), 3.46 (q, JZ6.8 Hz, 2H), 4.27
(m, 1H). IR (NaCl) 1669 cmK1 (C]C). MS (EI) 244 (MC).
HRMS calcd for C13H28O2Si 244.1858, found 244.1853.
Anal. Calcd for C13H28O2Si: C, 63.85; H, 11.56. Found: C,
63.90; H, 11.48.
1
4.5.1. 2,2-Dimethyl-3-decanone (14). A colorless oil. H
NMR (270 MHz, CDCl3) d 0.87 (t, JZ6.7 Hz, 3H), 1.13 (s,
9H), 1.27 (m, 8H), 1.57 (m, 2H), 2.46 (t, JZ7.3 Hz, 2H).
13C NMR (68 MHz, CDCl3) d 14.05, 22.59, 23.94, 26.39,
29.15, 29.29, 31.71, 36.42, 44.07, 216.10. IR (NaCl)
1707 cmK1 (C]C). MS (EI) 184 (MC). HRMS calcd for
C12H24O 184.1827, found 184.1819.
4.5.8. (Z)-2-Methyl-3-(trimethylsiloxy)-3-decene (22). A
colorless oil. H NMR (270 MHz, CDCl3) d 0.19 (s, 9H),
1
0.88 (t, JZ6.9 Hz, 3H), 1.03 (d, JZ6.7 Hz, 6H), 1.27–1.30
(m, 8H), 1.96–1.98 (m, 2H), 2.12–2.17 (m, 1H), 4.45 (dt,
JZ0.6, 6.9 Hz, 1H). IR (neat) 1669 cmK1 (C]C). MS (EI)
242 (MC). HRMS calcd for C14H30OSi 242.2066, found
242.2043. Anal. Calcd for C14H30OSi: C, 69.32, H, 12.49.
Found: C, 69.00; H, 12.58.
4.5.2. 2,2-Dimethyl-7-octen-3-one (15). A colorless oil. 1H
NMR (270 MHz, CDCl3) d 1.10 (s, 9H), 1.63 (t, JZ7.3 Hz,
2H), 2.00 (m, 2H), 2.46 (t, JZ7.3 Hz, 2H), 4.92–5.01 (m,
2H), 5.69–5.79 (m, 1H). 13C NMR (68 MHz, CDCl3) d
22.86, 26.35, 33.08, 35.48, 44.04, 114.95, 138.17, 215.73.
IR (NaCl) 1645 cmK1 (C]C), 1703 cmK1 (C]O). MS
(EI) 154 (MC). HRMS calcd for C10H18O 154.1357, found
154.1376.
4.5.9. (Z)-9-Chloro-3,8-dimethyl-4-(trimethylsiloxy)-4-
nonene (23). A colorless oil. H NMR (270 MHz, CDCl3)
1
d 0.18 (s, 9H), 0.99 (d, JZ6.8 Hz, 3H), 1.00 (d, JZ6.3 Hz,
3H), 1.17–1.34 (m, 2H), 1.43–1.57 (m, 2H), 1.78–2.10 (m,
4H), 3.37–3.53 (m, 2H), 4.39 (t, JZ7.0 Hz, 1H). 13C NMR
(68 MHz, CDCl3) d 0.78, 11.60, 17.69, 18.11, 22.81, 27.11,
34.04, 35.07, 41.38, 51.17, 105.91, 154.71. IR (NaCl)
1668 cmK1 (C]C). MS (EI) 276 (MC). HRMS calcd for
C14H29OSiCl 276.1676, found 276.1685. Anal. Calcd for
C14H29OSiCl: C, 60.70; H, 10.57. Found: C, 60.83; H,
10.74.
4.5.3. 2,2-Dimethyl-4-(3-propenyl)-7-octen-3-one (16). A
colorless oil. H NMR (270 MHz, CDCl3) d 1.13 (s, 9H),
1
1.41–1.54 (m, 1H), 1.61–1.74 (m, 1H), 1.94–2.15 (m, 3H),
2.25–2.35 (m, 1H), 2.95–3.04 (m, 1H), 4.94–5.04 (m, 4H),
5.62–5.83 (m, 2H). 13C NMR (68 MHz, CDCl3) d 26.36,
31.19, 31.55, 36.73, 44.44, 44.56, 114.98, 116.74, 135.97,
138.10, 217.91. IR (NaCl) 1640 cmK1 (C]C), 1702 cmK1
(C]O). MS (EI) 194 (MC). HRMS calcd for C13H22O
194.1670, found 194.1707. Anal. Calcd for C13H22O: C,
80.33; H, 11.43. Found: C, 80.11; H, 11.23.
4.5.10. (Z)-3-Methyl-4-(trimethylsiloxy)-4-tetradecene
(24). A colorless oil. H NMR (270 MHz, CDCl3) d 0.18
1
4.5.4. (Z)-2,2-Dimethyl-3-(trimethylsiloxy)-3-decene
(17). A colorless oil. H NMR (270 MHz, CDCl3) d 0.22
(s, 9H), 0.78–0.94 (m, 6H), 0.99 (d, JZ6.7 Hz, 3H), 1.18–
1.36 (m, 14H), 1.44–1.61 (m, 2H), 1.91–2.01 (m, 3H), 4.42
(t, JZ6.8 Hz, 1H). 13C NMR (68 MHz, CDCl3) d 0.80,
11.63, 14.10, 18.14, 22.70, 25.59, 27.19, 29.35, 29.49,
29.59, 29.63, 30.04, 31.94, 41.52, 106.82, 154.06. IR (NaCl)
1669 cmK1 (C]C). MS (EI) 298 (MC). HRMS calcd for
C18H38OSi 298.2692, found 298.2696.
1
(s, 9H), 0.80–0.90 (m, 3H), 1.03 (s, 9H), 1.21–1.36 (m, 8H),
1.89–2.00 (m, 2H), 4.50 (t, JZ6.7 Hz, 1H). 13C NMR
(68 MHz, CDCl3) d 14.08, 22.64, 26.27, 28.64, 29.19,
29.99, 31.82, 36.18, 104.27, 157.95. IR (NaCl) 1660 cmK1
(C]C). MS (EI) 256 (MC). HRMS calcd for C15H32OSi
256.2222, found 256.2218. Anal. Calcd for C15H32OSi: C,
70.12; H, 12.59. Found: C, 70.04; H, 12.76.
4.5.11. 2,2-Dimethyl-4-(propenyl)-3-decanone (19). A
solution of lithium enolate of b-lithio ketone 3a
(1.0 mmol) in THF (5 mL) was cooled to K78 8C, and
pentyl bromide (0.302 g, 2 mmol) was added. The reaction
4.5.5. (Z)-2,2-Dimethyl-3-(trimethylsiloxy)-3,10-undeca-
diene (18). A colorless oil. H NMR (270 MHz, CDCl3) d
1

3392
H. Nakahira et al. / Tetrahedron 61 (2005) 3383–3392
mixture was stirred at K20 8C for 1 h. After cooling to
K78 8C, HMPA (0.5 mL) and allyl bromide (0.360 g,
3 mmol) were added. The mixture was allowed to warm
to 25 8C and stirred for 1 h. The reaction mixture was
worked up as described in the general procedure. Flash
chromatography (SiO2) gave 2,2-dimethyl-4-(2-propenyl)-
3-decanone (19) (0.158 g, 70%) as a colorless oil.
References and notes
1. For leading reviews, see: (a) Hoppe, D.; Hense, T. Angew.
Chem. 1997, 36, 2282. (b) Marek, I.; Normant, J. F. Chem.
Rev. 1996, 96, 3241. (c) Beak, P.; Basu, A.; Gallagher, D. J.;
Park, T. S.; Thayumanavan, S. Acc. Chem. Res. 1996, 29, 552.
(d) Najera, C.; Yus, M. Curr. Org. Chem. 2003, 7, 867.
2. For a review, see: Thompson, C. M. Dianion Chemistry in
Organic Synthesis; CRC Press: Boca Raton, Florida, 1994.
3. Hubbard, J. S.; Harris, T. M. J. Am. Chem. Soc. 1980, 102, 2110.
4. (a) Kowalski, C. J.; O’Dowd, M. L.; Burke, M. C.; Fields,
K. W. J.Am. Chem. Soc. 1980, 102, 5411. (b) Kowalski, C. J.;
Lal, G. S. J.Am. Chem. Soc. 1986, 108, 5356.
1H NMR (270 MHz, CDCl3) d 0.86 (t, JZ6.5 Hz, 3H), 1.12
(s 9H), 1.23–1.58 (m, 10H), 2.03–2.33 (m, 2H), 2.90–2.97
(m, 1H), 4.95–5.03 (m, 2H), 5.61–5.74 (m, 1H) 13C NMR
(68 MHz, CDCl3) d 14.04, 22.59, 26.37, 27.63, 29.49,
31.69, 32.30, 36.93, 44.38, 45.37, 116.48, 136.30, 218.34.
IR (NaCl) 1640 cmK1 (C]C), 1703 cmK (C]O). MS (EI)
224 (MC). HRMS calcd for C15H28O (MC) 224.2140,
found 224.2150.
5. Goswami, R. J. Am. Chem. Soc. 1980, 102, 5973.
6. Ramig, K.; Bhupathy, M.; Cohen, T. J. Org. Chem. 1989, 54,
4404.
7. Nakahira, H.; Ryu, I.; Ikebe, M.; Kambe, N.; Sonoda, N.
Angew. Chem. 1991, 30, 177.
4.6. Reaction of ketone dilithio a,b-dianion 3a with
valeraldehyde
8. Ryu, I.; Nakahira, H.; Ikebe, M.; Sonoda, N.; Yamato, S.;
Komatsu, M. J. Am. Chem. Soc. 2000, 122, 1219.
9. (a) Ryu, I.; Ikebe, M.; Sonoda, N.; Yamato, S.; Yamamura, G.;
Komatsu, M. Tetrahedron Lett. 2000, 41, 5689. (b) Ryu, I.;
Ikebe, M.; Sonoda, N.; Yamato, S.; Yamamura, G.; Komatsu,
M. Tetrahedron Lett. 2002, 43, 1257.
To a solution of b-lithio ketone enolate 3a generated from
b-tributylstannyl ketone 1a (1 mmol) in THF (5 mL) at
K78 8C was added valeraldehyde (25) (0.086 g, 1 mmol) in
one portion. After the mixture was stirred at K78 8C for
15 min, water was added. The aqueous layer was extracted
with ether. The combined ether extracts were dried
over MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified PTLC (SiO2, ethyl
acetate/hexane (1:5)) to give aldol product 26 (94 mg, 47%)
and diol 27 (8 mg, 4%).
10. For reviews of b-acyl anion equivalents, see: (a) Seebach, D.
Angew. Chem., Int. Ed. Engl. 1979, 18, 239. (b) Werstiuk,
N. H. Tetrahedron 1983, 39, 205. (c) Stowell, J. C. Chem. Rev.
1984, 84, 409. (d) Hoppe, D. Angew. Chem., Int. Ed. Engl.
1984, 23, 932. (e) Hase, T. A. Umpoled Synthons; Wiley: New
York, 1987. (f) Kuwajima, I.; Nakamura, E. In Trost, B. M.,
Fleming, I., Eds.; Comprehensive Organic Synthesis;
Pergamon: Oxford, 1991; Vol. 2, pp 441–454.
4.6.1. 2,2-Dimethyl-6-hydroxydecane-3-one (26). A color-
less oil. H NMR (270 MHz, CDCl3) d 0.87–0.95 (m, 3H),
11. (a) Nakahira, H.; Ryu, I.; Ikebe, M.; Oku, Y.; Ogawa, A.;
Kambe, N.; Sonoda, N.; Murai, S. J. Org. Chem. 1992, 57, 17. (b)
Ryu, I.; Murai, S.; Sonoda, N. J.Org. Chem. 1986, 51, 2389.
12. Nakahira, H.; Ryu, I.; Ogawa, A.; Kambe, N.; Sonoda, N.
Organometallics 1990, 9, 277.
1
1.15 (s, 9H), 1.25–1.67 (m, 8H), 1.74–1.86 (m, 1H), 2.65 (t,
JZ6.8 Hz, 2H), 3.55 (bs, 1H). 13C NMR (68 MHz, CDCl3)
d 14.04, 22.69, 26.47, 27.84, 31.08, 32.99, 37.58, 44.22,
71.59, 217.04. IR (NaCl) 1703 cmK1 (C]O), 3429 cmK1
(OH). MS (EI) 200 (MC). HRMS calcd for C12H22O (MC-
H2O) 182.1670, found 182.1670.
13. Fu, G. C.; Nguyen, S.-B.T.; Grubbs, R. H. J. Am. Chem. Soc.
1993, 115, 9856.
14. For reviews, see: (a) Heathcock, C. H. In Modern Synthetic
Methods; Scheffold, R., Ed.; VCH: New York, 1992; Vol. 3,
pp 3–102. (b) Caine, D. In Trost, B. M., Fleming, I., Eds.;
Comprehensive Organic Synthesis; Pergamon: Oxford, 1991;
Vol. 3, pp 1–63.
4.6.2. 2,2-Dimethyl-3-vinyl-3,4-octanediol (27). A color-
less oil. H NMR (270 MHz, CDCl3) d 0.87–0.95 (m, 3H),
1
0.97 (s, 9H), 1.20–1.81 (m, 7H), 3.73 (bs, 2H), 5.22 (dd, JZ
2.0, 11.0 Hz, 1H), 5.33 (dd, JZ2.0, 17.0 Hz, 1H), 5.90 (dd,
JZ11.0, 17.0 Hz, 1H). 13C NMR (68 MHz, CDCl3) d 14.06,
25.11, 26.51, 28.71, 33.80, 46.50, 73.55, 80.28, 114.69,
137.96. IR (NaCl) 3425 cmK1 (OH). HRMS calcd for
C12H24O2 200.1776, found 200.1771.
15. (a) Colvin, E. W. Silicon in Organic Synthesis; Butterworth:
London, 1988. (b) Brownbridge, P. Synthesis 1983, 1. (c)
Brownbridge, P. Synthesis 1983, 85.
16. Such an ambident character was not observed on protonolysis
of dianion 3j with MeOH at K78 8C, which gave 3-nonanone
exclusively.
17. Cf.: for ambident characters of 1-alkoxy- or 1-siloxyallylic
anions, see: (a) Evans, D. A.; Andrews, G. C.; Buckwalter, B.
J. Am. Chem. Soc. 1974, 96, 5560. (b) Still, W. C.; Macdonald,
T. L. J. Am. Chem. Soc. 1974, 96, 5561. (c) Kato, M.; Mori, A.;
Oshino, H.; Enda, J.; Kobayashi, K.; Kuwajima, I. J. Am.
Chem. Soc. 1984, 106, 1773. (d) Chenard, B. L. Tetrahedron
Lett. 1986, 27, 2805.
Acknowledgements
This work was supported by Grant-in-Aid for Scientific
Research (B) from JSPS. We thank Dr. W. Ewan Hume and
Dr. Cathlleen M. Crudden for helpful discussions.