From cationic to anionic helicenes: New reactivity through umpolung

Article abstract of DOI:10.1021/jo200071n

Using a two-step reduction/metalation procedure, highly stable chiral carbenium ions are transformed into reactive carbanion intermediates. Interesting polar ketone and thioamide products are the results of this umpolung that occurs with complete retentio

Full text of DOI:10.1021/jo200071n

ARTICLE
pubs.acs.org/joc
From Cationic to Anionic Helicenes: New Reactivity through
Umpolung
David Conreaux, Nathalie Mehanna, Christelle Herse, and Jꢀer^ome Lacour*
Department of Organic Chemistry, University of Geneva, 30 Quai Ernest Ansermet, CH-1211 Geneva 4, Switzerland
S Supporting Information
b
ABSTRACT: Using a two-step reduction/metalation proce-
dure, highly stable chiral carbenium ions are transformed into
reactive carbanion intermediates. Interesting polar ketone and
thioamide products are the results of this umpolung that occurs
with complete retention of configuration of the helical
backbone.
Scheme 1. Umpolung Strategy via Carbanions 1ꢀ or 2ꢀ
mpolung or polarity inversion of functional groups is a
U
widely applied concept introduced by Corey and Seebach.1
It concerns all chemical modifications of functional groups that
lead to a formal reversal of polarity. Classical examples are the
transformations of electrophilic halogenoalcanes and ketones into
nucleophilic Grignard and dithiane reagents, respectively. In this
paper, we extend this notion to chiral electrophilic carbenium ions
1þ or 2þ (Scheme 1).2 We demonstrate that these chiral cationic
species can be transformed in two steps into reactive carbanions
1ꢀ or 2ꢀ onto which polar electrophilic reagents can be added—
and this with full conservation of the enantiomeric purity.
Previously, quinacridinium derivatives of type 1þ or 2þ have
been reported.3 These compounds are readily prepared in one
step by reactions of primary amines with tris(2,6-dimethoxyphe-
nyl)methylium ion. The reactions proceed through successive
ortho SNAr reactions of the methoxy substituents. Compounds
of type 1þ are highly stable carbocations (pKRþ ∼19). In terms
of stereochemistry, they adopt a twisted helical conformation
induced by the steric repulsion occurring between the methoxy
substituents in positions 1 and 13.3
Me, respectively) were treated with NaBH4 (EtOH, 20 °C) to
afford the reduced compounds 1-H and 2-H in excellent yields
(Scheme 2, 95ꢀ99%).5c With these adducts in hand, conditions
for the hydrogenꢀmetal exchange were established. The results
are summarized in Table 1 using, after metalation, benzylisothio-
cyanate 5 as electrophile.
KHMDS (potassium bis(trimethylsilyl)amide) and LiHMDS
(lithium bis(trimethylsilyl)amide) wereused initially, butevidence
could not be found of acidꢀbase reactivity (entries 1 and 2).
Stronger bases were then utilized, in particular, n-butyllithium.
Typically, solutions of 1-H in Et2O were treated at ꢀ78 °C with
n-BuLi. These solutions remained colorless until warmed to 0 °C.
A red color appeared that was assumed to be the carbanion. At
that temperature, electrophile 5 was added. The desired addition
product 3a was obtained in all cases (entries 3ꢀ9); yields varied
from moderate to good (42ꢀ85%). Several parameters were
tested to improve the yield including the number of equivalents
of base or of electrophile, temperature, and reaction time. In
short, the best procedure corresponds to a use of 2.0 equiv of n-
BuLi and of a large excess of benzyl isothiocyanate 5 (10 equiv).
Attempts with sec-butyllithium, with or without added TMEDA,
did not lead to a significant improvement (entry 10 and 11), and
tert-butyllithium afforded very little amount of 3a (entry 12).8
Compounds 1þ or 2þ exist, therefore, as helical P and M
enantiomers that are highly configurationally stable (Figure 1).4
These cationic helicenes react as electrophiles. Alkyl-, alkynyl-,
and aryllithium moieties add efficiently to the central carbon of
cations 1þ along with hydride reagents.5,6
Introduction of polar functional groups like carbonyl or
thioamide on these and related cations was, however, never
mentioned. A procedure for the making of compounds of type 3
or 4 (Scheme 1) was sought, but it was leading to a reactivity
problem. As mentioned, cations 1þ or 2þ are electrophilic
substrates, and groups like carbonyls are usually introduced in
addition reactions using electrophilic reagents as well. An
umpolung was necessary. However, rather than consider a
“classical” inversion of polarity of the electrophilic reagent, we
judged that it would be more general to switch the reactivity of
cations 1þ and form carbanions of type 1ꢀ instead (Scheme 1).7
Practically, a two-step metalation procedure was utilized to
achieve this goal. Salts [1þ][BF4] and [2þ][BF4] (R = n-Pr and
Received: January 12, 2011
Published: March 18, 2011
r
2011 American Chemical Society
2716
dx.doi.org/10.1021/jo200071n J. Org. Chem. 2011, 76, 2716–2722
|

The Journal of Organic Chemistry
ARTICLE
Table 2. Scope and Limitation of the Reaction
Figure 1. Dipropyl-1,13-dimethoxyquinacridinium 1þ: P and M
enantiomers.
Scheme 2. Synthesis of Reduced Products 1-H and 2-H
Table 1. Metalation Optimization study
entry
base (equiv)c
KHMDS (1.2)
solvent electrophile (5)d timee yieldf (%)
1a
2a
3a
4a
5a
6a
7a
8a
9a
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
6
6
120h
120
45
g
g
LiHMDS (3)
n-BuLi (1.2)
n-BuLi (1.2)
n-BuLi (1.2)
n-BuLi (2)
3
42
53
40
61
80
66
85
79
<10
<10
40
6
45
6
20
2
20
n-BuLi (2)
n-BuLi (2)i
6
20
6
20
n-BuLi (2)
10
6
20
20
10a s-BuLi (2)
11a s-BuLi (2)/ TMEDA (1) THF
12a t-BuLi (1.1)
13b n-BuLi (2)
c
a Isolated yields (%). b Complex mixture of inseparable products.
Starting material recovered.
6
20
Et2O
6
20
Et2O
10
20
a With 1-H. b With 2-H. c Base added at ꢀ78 °C (unless otherwise
noted) and reaction mixture stirred at 0 °C for 40 min. d Equivalents of
electrophile. e Reaction time (min, 0 °C) after the addition of 5. f Isolated
yields (%). g No reaction; recovery of the starting material. h 0 to 20 °C.
i Addition of the base at 0 °C.
good yields with other isothiocyanate reagents (71ꢀ83%, entries
1ꢀ3); the process was compatible with different R groups
attached to the N-atom. However, to our surprise, reactions
with analogous isocyanate reagents led to complex mixtures of
products (e.g., PhNCO, entry 4). On the contrary, reactions with
carbonate reagents (e.g., (PhO)2CO, entry 5) led to a complete
lack of reactivity. For the introduction of carbonyl groups, while
acid chlorides were unproductive (entries 6 and 7), anhydride
reagents afforded good yields of ketones in general (entries
8ꢀ11). Small- to medium-size alkyl chains (methyl to isopropyl)
were introduced successfully; a lower yield of the benzoyl
derivative was obtained. Finally, an excellent yield of 89% was
obtained with hexyl iodide as electrophile (entry 12); the
The procedure was also tested with 2-H. In this case, a lower yield
of thioamide was obtained (4a: 40% vs 3a: 85%); the lower
solubility in Et2O of the dimethyl-substituted 2-H was probably
the reason for this outcome.
The scope of the reaction was further explored with other
electrophiles. The results are summarized in Table 2 using 1-H as
substrate exclusively. First, several thioamides were obtained in
2717
dx.doi.org/10.1021/jo200071n |J. Org. Chem. 2011, 76, 2716–2722

The Journal of Organic Chemistry
ARTICLE
Scheme 3. Enantiospecific Reduction, Lithiation, and
Alkylation
Figure 3. Atropisomers of 3h and variable-temperature 1H NMR
spectra (500 MHz, CDCl3).
bond; this type of conformational isomerism is common in
triptycenes, 9-arylfluorenes, and other derivatives.11 Our interest
1
was raised by the room-temperature H NMR spectrum of 3h
that was showing broad signals for the two methoxy substituents
unlike the spectra of other compounds 3 at the same tempera-
ture. This situation was interpreted as an indication of two
possible orientations for the carbonyl substituent around the
C(sp3)ꢀC(sp2) bond (Figure 3).
Figure 2. ECD spectra of (P)-(þ)-1-H before (blue) and after (green)
deuteration (c 7.6 ꢁ 10ꢀ6 M, CH3CN, 20 °C).
1H NMR analysis of 3h at 253 K confirmed the slow rotation
of the ketone substituent on the NMR time scale as two sets of
signals are clearly observed. The two rotamers are present in a 4:1
ratio. Rather large differences are observed for the diastereotopic
methoxy groups (Figure 3, Δδ 0.13 (red) and 0.08 (blue) ppm,
CDCl3). Variable-temperature NMR experiments were then
performed, and the dynamic conformational isomerism was
characterized at elevated temperatures. Experimental values
for the different (mean) rates of interconversion were deter-
mined by line-shape analysis of the broadened exchange signals
(WinDNMR, see the Supporting Information) corresponding to
purpose of the reaction was to ascertain the exclusive formation
of the product of C6H13 addition and the absence of a butyl
derivative.9 All in all, softer electrophiles seem to perform better,
affording smoothly the desired addition products.10
While performing these reactions, we realized that chiral
cations 1þ and 2þ, and corresponding hydride derivatives 1-H
and 2-H, had been used as racemates only. This was prohibiting
the (likely) demonstration of a configurational stability for
anionic intermediates 1ꢀ or 2ꢀ. Care was thus taken to test
some reactions again using an enantiopure substrate.
an energy of activation in the range of 16.7 ((0.3) kcal molꢀ1
3
Compound (P)-(þ)-1-H was prepared from salt [(P)-1þ]
[PF6]3b using the same protocol as for rac-1-H. This derivative
was then deprotonated and reacted with benzyl isothiocyanate 5
under the standard conditions to afford (P)-(þ)-3a as a single
enantiomer (Scheme 3 and Supporting Information). After this
first evidence of configurational stability for the intermediate,
(P)-(þ)-1-H was reacted with n-BuLi again and the resulting red
solution treated with methanol-d4 to afford a quantitative deu-
teration at the reactive center and a global retention of config-
uration as evidenced by the optical rotation and ECD spectra
(Figure 2) measurements of (P)-(þ)-1-D. The umpolung
process therefore occurs with complete stereochemical integrity.
Finally, in the course of this study, we were able to evidence an
atropisomeric situation about the newly created C(sp3)ꢀC(sp2)
for the kinetic barrier.12
In conclusion, we have shown that highly stable chiral
carbenium ions can be transformed into reactive carbanion
intermediates in a simple, two-step procedure. The result of this
umpolung is the formation of interesting polar ketone and
thioamide products that are obtained in good yields and com-
plete retention of configuration.
’ EXPERIMENTAL SECTION
General Experimental Methods. NMR spectra were recorded
on 300, 400, or 500 MHz machines at rt (25 °C) unless otherwise noted.
1H NMR: chemical shifts are given in ppm relative to Me4Si with the
solvent resonance used as the internal standard (CD3CN δ 1.94 ppm;
2718
dx.doi.org/10.1021/jo200071n |J. Org. Chem. 2011, 76, 2716–2722

The Journal of Organic Chemistry
ARTICLE
CDCl3 δ 7.26 ppm). 13C NMR (125 or 101 MHz): chemical shifts were
given in ppm relative to Me4Si with the solvent resonance used as the
internal standard (CD3CN δ 118.3 and 1.3 ppm; CDCl3 δ 77.1 ppm).
19F NMR (282 MHz): chemical shifts are given in ppm relative to CFCl3
(δ 0). IR spectra were recorded using an ATR sampler and are reported
in wave numbers (cmꢀ1). Melting points (mp) were measured in open
capillary tubes and are uncorrected. Optical rotations were measured in a
thermostatted (20 °C) 10.0 cm long microcell at 589 nm (Na) or
435 nm (Hg) and are reported as follows: [R]Tλ (c (g/mol), solvent).
Circular dichroism spectra were recorded in a 1.0 cm quartz cell; λ
are given in nm and molar circular dichroic absorptions (Δε
(CH), 103.8 (CH), 103.6 (CH), 99.8 (CH), 55.3 (CH3), 54.1 (CH3),
46.7 (CH2), 46.5 (CH2), 31.4 (CH), 19.9 (CH2), 18.2 (CH2), 10.6
(CH3), 10.0 (CH3). HRMS (ESI): calcd for C27H31O2N2 415.238, obsd
415.2379.
1,3-Dimethoxy-5,9-dimethyl-9,13b-dihydro-5H-quino-
lino[2,3,4-kl]acridine (2-H). As described by the general procedure I
starting with [2þ][BF4]. Yield: 95%. Mp: 176.8 °C dec. IR: 2925, 2833,
1618, 1589, 1463, 1434, 1364, 1336, 1234, 1167, 1152, 1126, 1084, 1053,
821, 751, 730, 708, 675 cmꢀ1. 1H NMR (400 MHz, CDCl3): δ 7.22 (t,
J = 8.3 Hz, 1H), 7.09ꢀ7.15 (m, 2H), 6.72 (d, J = 8.0 Hz, 1H), 6.48ꢀ6.59
(m, 5H), 4.76 (s, 1H), 3.75 (s, 3H), 3.49 (s, 3H), 3.45 (s, 3H), 3.31 (s,
3H). 13C NMR (101 MHz, CDCl3): δ 160.0 (C), 157.1 (C), 146.8 (C),
145.9 (C), 142.1 (C), 139.7 (C), 127.6 (CH), 126.4 (CH), 125.6 (CH),
117.4 (C), 111.2 (C), 106.5 (CH), 106.0 (CH), 105.4 (CH), 105.1
(CH), 103.7 (CH), 101.2 (CH), 56.2 (CH3), 55.2 (CH3), 34.4 (CH3),
33.3 (CH3), 32.5 (CH). HRMS (ESI): calcd for C23H23O2N2 359.1754,
obsd 359.1755.
in cm2 mmolꢀ1). Electrospray mass spectra (ESIþ) were obtained by
3
the Department of Mass Spectroscopy of the University of Geneva.
HPLC analyses were performed using analytical Chiralpak IC or
Chiralcel OD-H (0.46 cm ꢁ25 cm) columns. Detection was performed
using a UV detector at 230 nm. Retention times (tR) are given in minutes
(min). All reactions involving air-sensitive compounds were carried out
under dry N2 or argon by means of an inert gas/vacuum double manifold
line and standard Schlenk techniques. n-BuLi was titrated using N-
benzylbenzamide in THF at ꢀ40 °C prior to use. CDCl3 was filtered on
basic alumina prior to use. Flash column chromatography was per-
formed with silica gel 40ꢀ63 μm or neutral alumina 50ꢀ200 μm.
Products 1þ and (P)-1þ were already described in the literature.3b
Synthesis of 1,13-Dimethoxy-5,9-dimethyl-5,9-dihydro-
quinolino[2,3,4-kl]acridin-13b-ylium Tetrafluoroborate [2þ]
[BF4]. At room temperature, the primary amine (methyl or propyl) (245
mmol, 25 equiv) was added to a solution of tris(2,6-dimethoxyphe-
nyl)carbenium tetrafluoroborate (9.8 mmol) in N-methyl-2-pyrrolidone
(NMP) (60 mL). The reaction mixture was stirred at 25 °C for 1 h,
heated at 90 °C for 2 h, and finally allowed to cool to rt. Addition of water
(∼80 mL) and a small amount of HBF4 afforded a precipitate, which was
filtered over a B€uchner funnel, washed with water and then several times
with Et2O, and collected. The titled compounds were further purified by
(i) dissolution of crude product in CH2Cl2 and (ii) selective precipita-
tion by addition of Et2O affording the desired dimethoxyquinacridinium
tetrafluoroborate salt. This final purification was performed until the
color of the solvent changed from reddish to colorless. The desired
product [2þ][BF4] was obtained in a good yield (75%). Mp: 280 °C dec.
IR (neat): 2950, 2841, 1605, 1579, 1498, 1345, 1252, 1088, 1035,
(þ)-(P)-1,13-Dimethoxy-5,9-dipropyl-9,13b-dihydro-5H-
quinolino[2,3,4-kl]acridine ((P)-1-H). As described by the general
procedure I starting with (P)-1þ. Yield: 93%. CD (CH3CN, 7.6 ꢁ 10ꢀ6
M, 20 °C): λ (Δε) 240.5 (25.3), 271 (24.9), 326.5 (40.9). [R]578
=
þ1014, [R]546 = þ1159, [R]436 = þ3261, [R]365 = þ8695 (c =
4.14.10ꢀ3, CH2Cl2, 20 °C).
General Procedure II for the Synthesis of the “Umpolung”
Products. To a colorless solution of 1-H or 2-H (0.16 mmol) in 2 mL of
dry Et2O was added n-BuLi (0.32 mmol, 2 equiv) at ꢀ78 °C. After a quick
warming to 0 °C, the color changed from colorless to light red to a dark
red-pink. The reaction mixture was stirred at 0 °C for 20ꢀ30 min before
the addition of the electrophile (1.6 mmol, 10 equiv). The mixture was
stirred at 0 °C for 20 min, quenched with water, and extracted with Et2O
three times. The organic layers were collected together, dried (MgSO4),
filtered, and concentrated in vacuo. The crude was then purified by flash
chromatography (Al2O3 neutral, AcOEt/pentane, 1/20) and/or on thin-
layer preparative chromatographic plates (Al2O3 neutral, AcOEt/pentane,
1/40) to afford the umpolung products as white solids.
N-Benzyl-1,13-dimethoxy-5,9-dipropyl-9,13b-dihydro-
5H-quinolino[2,3,4-kl]acridine-13b-carbothioamide (3a). As
described by the general procedure II starting with 1-H. Yield: 85%. Mp:
160.2 °C dec. IR: 3356, 2959, 2924, 2876, 1617, 1585, 1517, 1473, 1433,
1385, 1338, 1240, 1218, 1167, 1132, 1087, 1054, 839, 763, 749, 738,
699 cmꢀ1. 1H NMR (300 MHz, CDCl3): δ 7.57 (s, 1H), 7.26ꢀ7.33 (m,
3H), 7.11ꢀ7.20 (m, 5H), 6.76 (d, J = 8.2 Hz, 1H), 6.60 (t, J = 8.7 Hz,
2H), 6.50 (d, J = 8.1 Hz, 2H), 6.30 (d, J = 8.1 Hz, 1H), 4.78 (dd, J = 5.1
and 15.3 Hz, 1H), 4.43 (dd, J = 4.9 and 15.3 Hz, 1H), 3.73ꢀ3.89 (m,
4H), 3.32 (s, 3H), 3.30 (s, 3H), 1.63ꢀ1.94 (m, 4H), 1.06 (t, J = 7.4 Hz,
3H), 0.98 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, CDCl3): δ 207.7
(C), 160.8 (C), 159.2 (C), 145.3 (C), 143.1 (C), 140.3 (C), 138.7 (C),
136.7 (C), 128.6 (CH), 128.3 (CH), 127.9 (CH), 127.6 (CH), 127.3
(CH), 126.9 (CH), 115.5 (C), 113.8 (C), 112.3 (C), 107.1 (CH), 106.2
(CH), 105.9 (CH), 105.1 (CH), 104.8 (CH), 101.2 (CH), 56.0 (CH3),
55.5 (C), 54.4 (CH3), 50.5 (CH2), 48.6 (CH2), 48.0 (CH2), 20.8
(CH2), 19.9 (CH2), 11.8 (CH3), 11.1 (CH3). HRMS (ESI): calcd
C35H38N3O2S 564.2679, observed 564.2689.
1
762 cmꢀ1. H NMR (400 MHz, CDCl3): δ 8.02 (t, J = 8.5 Hz, 1H),
7.82ꢀ7.86 (m, 2H), 7.37 (dd, J = 8.7 and 12 Hz, 4H), 6.87 (d, J = 8.1 Hz,
2H), 4.01 (s, 6H), 3.68 (s, 6H). 13C NMR (101 MHz, CDCl3): δ 160.0
(C), 143.5 (C), 142.8 (C), 140.1 (C), 137.8 (CH), 137.0 (CH), 119.7
(C), 113.8 (C), 108.5 (CH), 105.7 (CH), 104.0 (CH), 56.4 (CH3), 38.1
(CH3). 19F NMR (282 MHz, CDCl3): δ ꢀ151.67 (20), ꢀ151.72 (80).
HRMS (ESI): calcd for C23H21O2N2 357.1597, observed 357.1598.
General Procedure I for the Reduction of Dimethoxyqui-
nacridinium Tetrafluoroborate Salts [1þ][BF4], [2þ][BF4] and
[(P)-1þ][PF6]. NaBH4 (2 equiv, 0.9 mmol) was slowly added at 25 °C
to a solution of the quinacridinium salts in EtOH (15 mL). After 0.5ꢀ1.5
h, the mixture was concentrated in vacuo, and the crude was purified by
flash chromatography (pentane/AcOEt, SiO2) to afford the products as
white solids.
1,13-Dimethoxy-5,9-dipropyl-9,13b-dihydro-5H-quino-
lino[2,3,4-kl]acridine (1-H). As described by the general procedure I
starting with [1þ][BF4]. Yield: 99%. Mp: 79.2 °C dec. IR: 2959, 2930,
2872, 2833, 1618, 1587, 1464, 1435, 1377, 1338, 1227, 1166, 1130, 1086,
1061, 752, 731, 677 cmꢀ1. 1H NMR (500 MHz, CDCl3): δ 7.17 (t, J =
8.3 Hz, 1H), 7.01ꢀ7.08 (m, 2H), 6.72 (d, J = 8.0 Hz, 1H), 6.40ꢀ6.53
(m, 5H), 4.67 (s, 1H), 3.85ꢀ3.91 (m, 2H), 3.58ꢀ3.77 (m, 2H), 3.72 (s,
3H), 3.38 (s, 3H), 1.87ꢀ1.96 (m, 2H), 1.74ꢀ1.85 (m, 2H), 0.99ꢀ1.05
(m, 6H). 13C NMR (126 MHz, CDCl3): δ 159.1 (C), 156.2 (C), 145.3
(C), 144.2 (C), 139.9 (C), 137.7 (C), 126.5 (CH), 125.1 (CH), 124.2
(CH), 118.0 (C), 111.4 (C), 109.9 (C), 105.9 (CH), 105.3 (CH), 104.1
(þ)-(P)-N-Benzyl-1,13-dimethoxy-5,9-dipropyl-9,13b-di-
hydro-5H-quinolino[2,3,4-kl]acridine-13b-carbothioamide
((P)-3a). As described by the general procedure II starting with (P)-1-
H. Yield: 62%. CD (CH3CN, c = 7 ꢁ 10ꢀ6 M, 20 °C): λ (Δε) 345
(20.2), 328 (31.4), 302.5 (ꢀ22.2), 279 (63.6), 260 (56.2), 238.5 (ꢀ6.2),
229 (10.3), 208 (ꢀ84.3), 198.5 (ꢀ65.0). [R]589 = þ893 (c = 7.4.10ꢀ4
M, CH3CN, 20 °C).
N-Benzyl-1,13-dimethoxy-5,9-dimethyl-9,13b-dihydro-
5H-quinolino[2,3,4-kl]acridine-13b-carbothioamide (4a).
As described by the general procedure II starting with 2-H. Yield:
40%. Mp: 74.3 °C dec. IR: 3350, 2920, 2831, 1618, 1585, 1518, 1470,
2719
dx.doi.org/10.1021/jo200071n |J. Org. Chem. 2011, 76, 2716–2722

The Journal of Organic Chemistry
ARTICLE
1433, 1374, 1341, 1247, 1223, 1170, 1129, 1087, 1052, 841, 761, 733,
697 cmꢀ1. 1H NMR (500 MHz, CDCl3): δ 7.54 (br s, 1H), 7.26ꢀ7.28
(m, 3H), 7.13ꢀ7.21 (m, 5H), 6.62ꢀ6.66 (m, 3H), 6.55 (d, J = 8.0 Hz,
1H), 6.44 (d, J = 7.8 Hz, 1H), 6.36 (d, J = 7.9 Hz, 1H), 4.91 (dd, J = 6.3,
15.1 Hz, 1H), 4.41 (dd, J = 4.3, 15.0 Hz, 1H), 3.49 (s, 3H), 3.44 (s,
3H), 3.38 (s, 3H), 3.25 (s, 3H). 13C NMR (126 MHz, CDCl3): δ
207.4 (C), 160.7 (C), 158.9 (C), 145.7 (C), 143.4 (C), 141.1 (C),
139.3 (C), 136.8 (C), 128.5 (CH), 128.2 (CH), 127.9 (CH), 127.6
(CH), 127.5 (CH), 127.1 (CH), 114.0 (C), 112.9 (C), 112.8 (C),
106.5 (CH), 106.2 (CH), 106.1 (CH), 105.6 (CH), 103.6 (CH),
101.6 (CH), 55.8 (CH3), 55.3 (C), 54.7 (CH3), 50.2 (CH2), 34.5
(CH3), 33.9 (CH3). HRMS (ESI): calcd C31H30N3O2S 508.2053,
observed 508.2078.
1,13-Dimethoxy-N,5,9-tripropyl-9,13b-dihydro-5H-quino-
lino[2,3,4-kl]acridine-13b-carbothioamide (3b). As described
by the general procedure II starting with 1-H. Yield: 83%. Mp: 73.3 °C
dec. IR: 3359, 2957, 2929, 2871, 2831, 1617, 1584, 1472, 1459, 1432,
1390, 1351, 1220, 1168, 1130, 1088, 1058, 839, 758, 703 cmꢀ1. 1H NMR
(500 MHz, CDCl3): δ 7.32 (s, 1H), 7.18 (m, 2H), 7.12 (t, J = 8.2 Hz,
1H), 6.78 (br d, J = 8.1 Hz, 1H), 6.61 (br d, J = 8.3 Hz, 1H), 6.55ꢀ6.58
(m, 2H), 6.49 (d, J = 7.9 Hz, 1H), 6.35 (br d, J = 8.0 Hz, 1H), 3.72ꢀ3.87
(m, 4H), 3.62 (s, 3H), 3.40ꢀ3.47 (m, 1H), 3.37 (s, 3H), 3.23ꢀ3.30 (m,
1H), 1.68ꢀ1.89 (m, 4H), 1.46 (m, 2H), 1.05 (t, J = 7.4 Hz, 3H), 1.00 (t,
J = 7.4 Hz, 3H), 0.82 (t, J = 7.5 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ
206.8 (C), 160.8 (C), 159.2 (C), 145.3 (C), 142.9 (C), 140.3 (C), 138.7
(C), 128.1 (CH), 127.2 (CH), 126.8 (CH), 115.3 (C), 113.9 (C), 112.5
(C), 107.0 (CH), 106.1 (CH), 105.9 (CH), 105.0 (CH), 104.7 (CH),
101.3 (CH), 56.0 (CH3), 55.3 (C), 54.7 (CH3), 48.5 (CH2), 47.9
(CH2), 47.7 (CH2), 21.1 (CH2), 20.6 (CH2), 19.8 (CH2), 11.7 (CH3),
11.5 (CH3), 11.0 (CH3). HRMS (ESI): calcd C31H38N3O2S 516.2679,
obsd 516.2679.
1,13-Dimethoxy-N-phenyl-5,9-dipropyl-9,13b-dihydro-
5H-quinolino[2,3,4-kl]acridine-13b-carbothioamide (3c). As
described by the general procedure II starting with 1-H. Yield: 80%. Mp:
92.9 °C dec. IR: 3317, 2958, 2933, 2872, 2831, 1617, 1585, 1473, 1461,
1432, 1374, 1230, 1167, 1130, 1087, 1058, 756, 726, 690 cmꢀ1. 1H NMR
(500 MHz, CDCl3): δ 8.99 (s, 1H), 7.63 (d, J = 7.7 Hz, 2H), 7.24ꢀ7.27
(m, 3H), 7.18 (t, J = 8.3 Hz, 1H), 7.09ꢀ7.15 (m, 2H), 6.83 (d, J = 8.1 Hz,
1H), 6.58ꢀ6.63 (m, 3H), 6.50 (d, J = 8.0 Hz, 1H), 6.35 (d, J = 8.0 Hz,
1H), 3.72ꢀ3.89 (m, 4H), 3.56 (s, 3H), 3.42 (s, 3H), 1.84ꢀ1.90 (m, 2H),
1.53ꢀ1.66 (m, 2H), 1.05 (t, J = 7.4 Hz, 3H), 0.80 (t, J = 7.4 Hz, 3H). 13C
NMR (126 MHz, CDCl3): δ 206.7 (C), 161.0 (C), 159.3 (C), 145.3
(C), 142.9 (C), 140.3 (C), 139.1 (C), 139.0 (C), 128.5 (CH), 128.3
(CH), 127.7 (CH), 126.9 (CH), 125.4 (CH), 121.4 (CH), 115.98 (C),
114.0 (C), 113.1 (C), 107.4 (CH), 106.2 (CH), 106.0 (CH), 105.1
(CH), 104.8 (CH), 101.5 (CH), 57.4 (C), 56.0 (CH3), 55.4 (CH3), 48.5
(CH2), 48.1 (CH2), 20.6 (CH2), 19.9 (CH2), 11.7 (CH3), 11.1 (CH3).
HRMS (ESI): calcd for C34H36N2O3S 550.2522, obsd 550.2531.
N-(3,5-Bis(trifluoromethyl)phenyl)-1,13-dimethoxy-5,9-
dipropyl-9,13b-dihydro-5H-quinolino[2,3,4-kl]acridine-
13b-carbothioamide (3d). As described by the general procedure II
starting with 1-H. Yield: 71%. Mp: 92.9 °C dec. IR: 3312, 2963, 2929,
2880, 2839, 1618, 1586, 1544, 1473, 1437, 1378, 1350, 1274, 1242, 1219,
1167, 1127, 1058, 883, 762, 729, 697, 680 cmꢀ1. 1H NMR (500 MHz,
CDCl3): δ 9.11 (s, 1H), 8.11 (s, 2H), 7.60 (s, 1H), 7.31 (t, J = 8.2 Hz,
1H), 7.21 (t, J = 8.3 Hz, 1H), 7.15 (t, J = 8.2 Hz, 1H), 6.85 (d, J = 8.0 Hz,
1H), 6.65 (dd, J = 4.4, 8.1 Hz, 2H), 6.60 (d, J = 8.3 Hz, 1H), 6.51 (d,
J = 8.0 Hz, 1H), 6.37 (d, J = 7.9 Hz, 1H), 3.72ꢀ3.86 (m, 4H), 3.58 (s,
3H), 3.44 (s, 3H), 1.82ꢀ1.90 (m, 2H), 1.52ꢀ1.62 (m, 2H), 1.06 (t,
J = 7.4 Hz, 3H), 0.83 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, CDCl3):
δ 210.4 (C), 160.8 (C), 159.2 (C), 145.3 (C), 143.0 (C), 140.2 (C),
140.1 (C), 138.9 (C), 131.8 (q, J = 33.6 Hz, 2C), 128.6 (CH), 128.2
(CH), 127.2 (CH), 122.9 (q, J = 272.8 Hz, 2C), 121.5 (d, J = 3.4 Hz,
CH), 118.7 (q, J = 3.4 Hz, 2CH), 115.9 (C), 113.6 (C), 112.8 (C), 107.5
(CH), 106.4 (CH), 106.2 (CH), 105.3 (CH), 104.9 (CH), 101.3 (CH),
57.7 (C), 55.9 (CH3), 55.3 (CH3), 48.5 (CH2), 48.0 (CH2), 20.9
(CH2), 19.8 (CH2), 11.6 (CH3), 11.1 (CH3). HRMS (ESI): calcd for
C36H34F6N3O2S 686.2270, obsd 686.2302.
1-(1,13-Dimethoxy-5,9-dipropyl-9,13b-dihydro-5H-quino-
lino[2,3,4-kl]acridin-13b-yl)ethanone (3e). As described by the
general procedure II starting with 1-H. Yield: 71%. Mp: 163.3 °C dec.
IR: 2950, 2873, 2830, 1725, 1585, 1474, 1434, 1393, 1341, 1241, 1218,
1170, 1131, 1089, 1059, 877, 762, 734, 710 cmꢀ1. 1H NMR (500 MHz,
CDCl3): δ 7.21 (t, J = 7.8 Hz, 1H), 7.15 (t, J = 8.2 Hz, 1H), 7.07 (t, J =
8.1 Hz, 1H), 6.79 (dd, J = 0.8, 8.2 Hz, 1H), 6.54ꢀ6.57 (m, 2H),
6.48ꢀ6.49 (m, 2H), 6.37 (d, J = 8.1 Hz, 1H), 3.61ꢀ3.83 (m, 4H), 3.61
(s, 3H), 3.35 (s, 3H), 1.79ꢀ1.87 (m, 7H), 1.05 (t, J = 7.4 Hz, 3H), 1.00
(t, J = 7.1 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 196.9 (C), 161.3
(C), 157.8 (C), 145.0 (C), 143.2 (C), 140.8 (C), 138.8 (C), 129.0
(CH), 127.4 (CH), 126.5 (CH), 115.5 (C), 110.6 (C), 109.1 (C), 107.6
(CH), 106.5 (CH), 105.7 (CH), 105.3 (CH), 104.8 (CH), 101.2 (CH),
56.1 (CH3), 54.7 (CH3), 54.4 (C), 48.2 (CH2), 48.1 (CH2), 25.7
(CH3), 20.5 (CH2), 19.8 (CH2), 11.8 (CH3), 11.0 (CH3). HRMS
(ESI): calcd C29H33N2O3 457.2485, obsd 457.2481.
1-(1,13-Dimethoxy-5,9-dipropyl-9,13b-dihydro-5H-quino-
lino[2,3,4-kl]acridin-13b-yl)propan-1-one (3f). As described by
the general procedure II starting with 1-H. Yield: 77%. Mp: 65 °C dec.
IR: 2960, 2937, 2872, 2831, 1726, 1613, 1585, 1471, 1435, 1373, 1238,
1217, 1169, 1131, 1089, 1059, 867, 762, 717 cmꢀ1. 1H NMR (500 MHz,
CDCl3): δ 7.20 (t, J = 8.1 Hz, 1H), 7.15 (t, J = 8.1 Hz, 1H), 7.07 (t, J =
8.2 Hz, 1H), 6.79 (dd, J = 8.2, 0.7 Hz, 1H), 6.54ꢀ6.57 (m, 2H), 6.47 (d, J
= 8.1 Hz, 2H), 6.35 (d, J = 8.0 Hz, 1H), 3.65ꢀ3.84 (m, 4H), 3.59 (s, 3H),
3.35 (s, 3H), 2.12ꢀ2.23 (m, 2H), 1.78ꢀ1.88 (m, 4H), 1.06 (t, J = 7.4 Hz,
3H), 1.01 (t, J = 7.4 Hz, 3H), 0.71 (br s, 3H). 13C NMR (126 MHz,
CDCl3): δ 199.8 (C), 161.1 (C), 157.7 (C), 144.9 (C), 143.2 (C), 140.9
(C), 138.9 (C), 128.9 (CH), 127.3 (CH), 126.3 (CH), 115.4 (C), 110.7
(C), 108.8 (C), 107.5 (CH), 106.4 (CH), 105.6 (CH), 105.1 (CH),
104.7 (CH), 101.0 (CH), 56.0 (CH3), 54.6 (CH3), 54.1 (C), 48.2
(CH2), 48.0 (CH2), 30.7 (CH2), 20.5 (CH2), 19.8 (CH2), 11.7 (CH3),
11.0 (CH3), 10.0 (CH3). HRMS (ESI): calcd C30H35N2O3 471.2642,
obsd 471.2639.
1-(1,13-Dimethoxy-5,9-dipropyl-9,13b-dihydro-5H-quino-
lino[2,3,4-kl]acridin-13b-yl)-2-methylpropan-1-one (3g). As
described by the general procedure II starting with 1-H. Yield: 77%. Mp:
69.3 °C dec. IR: 2962, 2933, 2872, 2831, 1722, 1611, 1585, 1472, 1436,
1
1374, 1240, 1219, 1169, 1132, 1089, 1061, 1037, 762, 708 cmꢀ1. H
NMR (500 MHz, CDCl3) δ 7.21 (t, J = 8.3 Hz, 1H), 7.14 (t, J = 8.2 Hz,
1H), 7.06 (t, J = 8.2 Hz, 1H), 6.75ꢀ6.80 (m, 1H), 6.53ꢀ6.57 (m, 2H),
6.46 (dd, J = 2.1 Hz and J = 8.2 Hz, 2H), 6.33 (d, J = 7.7 Hz, 1H),
3.62ꢀ3.87 (m, 4H), 3.57 (s, 3H), 3.35 (s, 3H), 2.99 (hept, J = 6.7 Hz,
1H), 1.69ꢀ1.99 (m, 4H), 1.04 (dt, J = 7.4, J = 7.5 Hz, 6H), 0.64 (d, J =
6.6 Hz, 3H), 0.48 (d, J = 6.7 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ
202.1 (C), 161.3 (C), 157.9 (C), 144.9 (C), 144.3 (C), 141.4 (C), 139.4
(C), 129.2 (CH), 127.8 (CH), 126.5 (CH), 115.2 (C), 110.2 (C), 107.9
(CH), 107.8 (C), 106.6 (CH), 105.8 (CH), 105.0 (CH), 104.9 (CH),
100.8 (CH), 56.2 (CH3), 54.6 (CH3), 54.5 (C), 48.5 (CH2), 48.4
(CH2), 36.9 (CH), 21.8 (CH3), 20.9 (CH2), 20.1 (CH2), 12.0 (CH3),
11.2 (CH3). HRMS (ESI): calcd for C31H37N2O3 485.2798, obsd
485.2797.
(1,13-Dimethoxy-5,9-dipropyl-9,13b-dihydro-5H-quino-
lino[2,3,4-kl]acridin-13b-yl)(phenyl)methanone (3h). As de-
scribed by the general procedure II starting with 1-H. Yield: 26%. Mp:
70.9 °C dec. IR: 2959, 2930, 2873, 2834, 1693, 1584, 1470, 1435, 1381,
1239, 1215, 1170, 1131, 1089, 1060, 836, 761, 730, 696 cmꢀ1. 1H NMR
(400 MHz, THF, 50 °C): δ 7.26 (br d, J = 7.3 Hz, 1H), 6.90ꢀ7.07 (m,
6H), 6.70 (br d, J = 6.8 Hz, 1H), 6.49ꢀ6.55 (m, 3H), 6.43 (d, J = 8.0 Hz,
1H), 6.23 (d, J = 8.0 Hz, 1H), 3.82ꢀ3.90 (m, 1H), 3.71ꢀ3.79 (m, 1H),
3.62 (br s, 2H), 3.44 (s, 3H), 3.28 (s, 3H), 1.81 (m, 2H), 1.71 (br s, 2H),
2720
dx.doi.org/10.1021/jo200071n |J. Org. Chem. 2011, 76, 2716–2722

The Journal of Organic Chemistry
ARTICLE
1.03 (t, J = 7.4 Hz, 3H), 0.90 (t, J = 6.9 Hz, 3H). 13C NMR (126 MHz,
CDCl3, 50 °C): δ 189.2 (C), 160.9 (C), 157.9 (C), 145.9 (C), 144.1
(C), 140.5 (C), 139.5 (C), 138.8 (C), 129.0 (CH), 128.6 (CH), 128.4
(CH), 126.9 (CH), 126.5 (CH), 125.7 (CH), 117.3 (C), 111.86 (C),
107.5 (CH), 106.3 (CH), 105.4 (CH), 104.9 (CH), 104.6 (CH), 100.9
(CH), 78.3 (C), 55.4 (CH3), 53.5 (CH3), 53.3 (C), 47.8 (CH2), 47.4
(CH2), 20.3 (CH2), 19.6 (CH2), 10.9 (CH3), 10.1 (CH3). HRMS
(ESI): calcd C34H35O3N2 519.2642, obsd 519.2649.
13b-Hexyl-1,13-dimethoxy-5,9-dipropyl-9,13b-dihydro-
5H-quinolino[2,3,4-kl]acridine (6). As described by the general
procedure II starting with 1-H. Yield: 89%. Mp: 107.4ꢀ110.5 °C dec. IR:
2955, 2923, 2870, 1612, 1584, 1473, 1458, 1434, 1379, 1347, 1220, 1165,
1132, 1094, 1059, 781, 733, 711 cmꢀ1. 1H NMR (400 MHz, CDCl3): δ
7.22 (t, J = 8.3 Hz, 1H), 7.10ꢀ7.15 (m, 2H), 6.84 (d, J = 7.5 Hz, 1H),
6.49ꢀ6.63 (m, 5H), 3.99ꢀ4.03 (m, 2H), 3.79 (s, 3H), 3.71ꢀ3.85 (m,
2H), 3.36 (s, 3H), 2.21ꢀ2.28 (m, 1H), 2.09ꢀ2.16 (m, 1H), 2.01ꢀ2.08
(m, 2H), 1.84ꢀ1.90 (m, 2H), 1.00ꢀ1.16 (m, 12H), 0.83ꢀ0.90 (m, 1H),
0.79 (t, J = 7.0 Hz, 3H), 0.65ꢀ0.76 (m, 1H). 13C NMR (101 MHz,
CDCl3): δ 161.2 (C), 157.9 (C), 143.5 (C), 141.9 (C), 140.7 (C), 139.2
(C), 127.1 (CH), 125.9 (CH), 125.2 (CH), 119.3 (C), 113.8 (C), 113.1
(C), 107.3 (CH), 106.5 (CH), 105.2 (CH), 104.9 (CH), 104.1 (CH),
101.5 (CH), 56.6 (CH3), 54.9 (CH3), 48.8 (CH2), 48.1 (CH2), 40.9
(C), 34.0 (CH2), 31.4 (CH2), 29.4 (CH2), 25.6 (CH2), 22.5 (CH2),
20.3 (CH2), 19.9 (CH2), 14.1 (CH3), 12.0 (CH3), 11.0 (CH3). HRMS
(ESI): calcd C33H43N2O2 499.3319, obsd 499.3332.
’ REFERENCES
(1) (a) Corey, E. J.; Seebach, D. Angew. Chem., Int. Ed. 1965, 4, 1075.
(b) Seebach, D. Angew. Chem., Int. Ed. 1969, 8, 639. (c) Seebach, D.
Synthesis 1969, 1969, 17. (d) Seebach, D.; Corey, E. J. J. Org. Chem. 1975,
40, 231. (e) Seebach, D. Angew. Chem., Int. Ed. 1979, 18, 239.
(2) (a) Laursen, B. W.; Krebs, F. C. Chem.—Eur. J. 2001, 7, 1773. (b)
Laursen, B. W.; Krebs, F. C. Angew. Chem., Int. Ed. 2000, 39, 3432.
(3) (a) Herse, C.; Bas, D.; Krebs, F. C.; B€urgi, T.; Weber, J.;
Wesolowski, T.; Laursen, B. W.; Lacour, J. Angew. Chem., Int. Ed.
2003, 42, 3162. (b) Laleu, B.; Mobian, P.; Herse, C.; Laursen, B. W.;
Hopfgartner, G.; Bernardinelli, G.; Lacour, J. Angew. Chem., Int. Ed.
2005, 44, 1879.
(4) For reviews on helicenes and heterohelicenes, see: (a) Strained
Hydrocarbons; Starꢀy, I., Starꢀa, I. G., Dodziuk, H., Eds.; Wiley-VCH:
Weinheim, 2009; p 166. (b) Rajca, A.; Rajca, S.; Pink, M.; Miyasaka, M.
Synlett 2007, 2007, 1799.(c) Functional Organic Materials: Syntheses,
Strategies and Applications; Rajca, A.; Miyasaka, M., M€uller, T. J. J., Bunz,
U. H. F., Eds.; Wiley-VCH: Weinheim, 2007; p 543. (d) Collins, S. K.;
Vachon, M. P. Org. Biomol. Chem. 2006, 4, 2518. (e) Urbano, A. Angew.
Chem., Int. Ed. 2003, 42, 3986. (f) Katz, T. J. Angew. Chem., Int. Ed. 2000,
39, 1921. (g) Meurer, K. P.; V€ogtle, F. Top. Curr. Chem. 1985, 127, 1.
(5) For applications of products of nucleophilic additions on related
highly stable carbenium ions, see: (a) Mobian, P.; Banerji, N.; Bernardinelli,
G.; Lacour, J. Org. Biomol. Chem. 2006, 4, 224. (b) Laleu, B.; Machado,
M. S.; Lacour, J. Chem. Commun. 2006, 2786. (c) Guin, J.; Besnard, C.;
Pattison, P.; Lacour, J. Chem. Sci. 2011, 2, 425.
(6) (a) Lofthagen, M.; Chadha, R.; Siegel, J. S. J. Am. Chem. Soc.
1991, 113, 8785. (b) Lofthagen, M.; Clark, R. V.; Baldridge, K. K.; Siegel,
J. S. J. Org. Chem. 1992, 57, 61. (c) Lofthagen, M.; VernonClark, R.;
Baldridge, K. K.; Siegel, J. S. J. Org. Chem. 1992, 57, 61. (d) Lofthagen,
M.; Siegel, J. S. J. Org. Chem. 1995, 60, 2885. (e) Lofthagen, M.; Siegel,
J. S.; Hackett, M. Tetrahedron 1995, 51, 6195. (f) Laursen, B. W.; Krebs,
F. C.; Nielsen, M. F.; Bechgaard, K.; Christensen, J. B.; Harrit, N. J. Am.
Chem. Soc. 1998, 120, 12255. (g) Baisch, B.; Raffa, D.; Jung, U.;
Magnussen, O. M.; Nicolas, C.; Lacour, J.; Kubitschke, J.; Herges, R.
J. Am. Chem. Soc. 2009, 131, 442. (h) Narasimhan, S. K.; Kerwood, D. J.;
Wu, L.; Li, J.; Lombardi, R.; Freedman, T. B.; Luk, Y.-Y. J. Org. Chem.
2009, 74, 7023. (i) Guin, J.; Besnard, C.; Lacour, J. Org. Lett. 2010,
12, 1748. (j) Nicolas, C.; Bernardinelli, G.; Lacour, J. J. Phys. Org. Chem.
2010, 23, 1049.
(þ)-(P)-1, 13-Dimethoxy-5, 9-dimethyl-9,13b-dihydro-5D-
quinolino[2,3,4-kl]acridine ((P)-1-D). As described by the general
procedure II starting with (P)-1-H. Yield: 83%. Mp: 72.4 °C dec. IR:
2958, 2924, 2868, 2831, 1618, 1587, 1462, 1435, 1377, 1336, 1227, 1168,
1131, 1064, 749, 732 cmꢀ1. 1H NMR (500 MHz, CDCl3): δ 7.19 (t, J =
8.3 Hz, 1H), 7.03ꢀ7.09 (m, 2H), 6.74 (d, J = 8.1 Hz, 1H), 6.42ꢀ6.45
(m, 2H), 6.50ꢀ6.54 (m, 3H), 3.86ꢀ3.93 (m, 2H), 3.72ꢀ3.80 (m, 1H),
3.72 (s, 3H), 3.60ꢀ3.66 (m, 1H), 3.39 (s, 3H), 1.89ꢀ1.96 (m, 2H),
1.77ꢀ1.83 (m, 2H), 1.01ꢀ1.06 (m, 6H). 13C NMR (126 MHz, CDCl3):
δ 160.2 (C), 157.2 (C), 146.3 (C), 145.3 (C), 140.9 (C), 138.8 (C),
127.5 (CH), 126.2 (CH), 125.3 (CH), 119.0 (C), 112.4 (C), 110.9 (C),
107.0 (CH), 106.4 (CH), 105.2 (CH), 104.9 (CH), 104.7 (CH), 100.9
(CH), 56.3 (CH3), 55.2 (CH3), 47.8 (CH2), 47.6 (CH2), 21.0 (CH2),
19.3 (CH2), 11.70 (CH3), 11.1 (CH3). HRMS (ESI): calcd for
C27H30DO2N2 416.2458, obsd 416.2474. CD (CH3CN, 7.6 ꢁ 10ꢀ6
(7) Such an approach was partially substantiated by Laursen in his
electrochemical study of cations 1þ. See: Laursen, B. W. Ph.D. Thesis,
Risø National Laboratory, Roskilde, Denmark, and Department of
Chemistry, University of Copenhagen, 2001.
M, 20 °C): λ (Δε) 240.5 (25.3), 271 (24.9), 326.5 (40.9). [R]589
þ768 (c = 7.6.10ꢀ4, CH3CN, 20 °C).
=
(8) Formation of anion 1ꢀ was also attempted by direct reduction of
cation 1þ with LDBB (THF, ꢀ78 °C). After 30 min, isocyanate 5 was
added (ꢀ78 to 0 °C), and after workup (H2O, extraction), product 3a
was obtained in low yield (<10%) together with traces of reduced
derivative 1-H.
’ ASSOCIATED CONTENT
S
Supporting Information. HPLC data; ECD spectra;
b
(9) A product of butyl addition would have arise most probably from
an in situ oxidation of the carbanion to the radical or carbocationic
species which would have reacted with the excess of BuLi reagent.
(10) To rationalize this observation, an intriguing possibility is to
consider an electrophile-dependent stereocontrol; soft ((RCO)2O,
RNCS) and hard (RCOCl, RNCO) reagents leading to preferred
retention and inversion of configuration of the reactive benzylic sp3 center
respectively. In the latter case, the transformation is essentially impossible
due to the strain that it would induce on the heliccal framework. For
examples of electrophile-dependent stereocontrol in the context of
stabilized alkyllithiums, see: Hammerschmidt, F.; Hanninger, A.; Simov,
B. P.; V€ollenkle, H.; Werner, A. Eur. J. Org. Chem. 1999, 3511. Derwing,
C.; Frank, H.; Hoppe, D. Eur. J. Org. Chem. 1999, 3519.
variable-temperature NMR spectra and kinetic barrier determi-
nation; and H, 13C, and 19F NMR and HRMS spectra of all
1
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: jerome.lacour@unige.ch.
’ ACKNOWLEDGMENT
(11) (a) Oki, M. Top. Stereochem. 1983, 14, 1. (b) Oki, M. Acc. Chem.
Res. 1984, 17, 154.(c) Oki, M. Chemistry of Rotational Isomers; Springer-
Verlag: New York, 1993. (d) Oki, M. Recent Advances in Atropisomerism;
John Wiley & Sons, Inc.: New York, 2007. (e) Oki, M.; Nakamura, N.
Bull. Chem. Soc. Jpn. 1971, 44, 1880. (f) Nakamura, M.; Oki, M.
We are grateful for financial support for this work by the Swiss
National Science Foundation. The authors also acknowledge the
contributions of the Sciences Mass Spectrometry (SMS) plat-
form at the Faculty of Sciences (University of Geneva).
2721
dx.doi.org/10.1021/jo200071n |J. Org. Chem. 2011, 76, 2716–2722

The Journal of Organic Chemistry
ARTICLE
Tetrahedron Lett. 1974, 505. (g) Roussel, C.; Blaive, B.; Gallo, R.;
Metzger, J.; Sandstroem, J. Org. Magn. Reson. 1980, 14, 166. (h)
Rubiralta, M.; Jaime, C.; Feliz, M.; Giralt, E. J. Org. Chem. 1990,
55, 2307. (i) Jaime, C.; Virgili, A.; Claramunt, R. M.; Lopez, C.; Elguero,
J. J. Org. Chem. 1991, 56, 6521. (j) Lomas, J. S.; Anderson, J. E. J. Org.
Chem. 1995, 60, 3246. (k) Lomas, J. S.; Adenier, A. J. Chem. Soc., Perkin
Trans. 2 2001, 1051. (l) Boiadjiev, S. E.; Lightner, D. A. Tetrahedron:
Asymmetry 2002, 13, 1721. (m) Hou, Y.; Meyers, C. Y. J. Org. Chem.
2004, 69, 1186. (n) Casarini, D.; Coluccini, C.; Lunazzi, L.; Mazzanti, A.
J. Org. Chem. 2005, 70, 5098. (o) Damodaran, K.; Nielsen, S. D.; Geib,
S. J.; Zhang, W.; Lu, Y. M.; Curran, D. P. J. Org. Chem. 2009, 74, 5481.
(p) Murrison, S.; Glowacki, D.; Einzinger, C.; Titchmarsh, J.; Bartlett, S.;
McKeever-Abbas, B.; Warriner, S.; Nelson, A. Chem.—Eur. J. 2009,
15, 2185.
(12) The activation parameters (ΔHq, ΔSq, and ΔGq) for the mean
dynamic barrier have been calculated by using Arrhenius plots (first-
order kinetics, Ln k vs 1/T) and the Eyring equation. Values are reported
in the Supporting Information.
2722
dx.doi.org/10.1021/jo200071n |J. Org. Chem. 2011, 76, 2716–2722