New pyridine N-oxides as chiral organocatalysts in the asymmetric allylation of aromatic aldehydes

Article abstract of DOI:10.1016/j.tet.2008.08.084

Asymmetric allylation of aromatic aldehydes 1 with allyltrichlorosilane (2) can be catalyzed by new terpene-derived bipyridine N,N′-dioxides 12-15 and an axially chiral biisoquinoline dioxide 17b with good enantioselectivities. Dioxides have been found to be more reactive catalysts than their monooxide counterparts. Crown Copyright

Full text of DOI:10.1016/j.tet.2008.08.084

Tetrahedron 64 (2008) 11335–11348
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journal homepage: www.elsevier.com/locate/tet
New pyridine N-oxides as chiral organocatalysts in the asymmetric allylation
of aromatic aldehydes
, ,
,
z
a,
x
Andrei V. Malkova y, Mary-Margaret Westwater a, Andrey Gutnov b , Pedro Ramırez-Lopez
,
*
´
´
a
a,
{
c
d
e
´ ´
ˇ´
´
ˇ
´
Frederic Friscourt , Aneta Kadlcıkova , Jana Hodacova , Zoran Rankovic , Martin Kotora ,
a,
*
ˇ
´
Pavel Kocovsky
a Department of Chemistry, WestChem, Joseph Black Building, University of Glasgow, Glasgow G12 8QQ, Scotland, UK
b Leibniz Institute of Catalysis, University of Rostock, D-18055 Rostock, Germany
c Department of Organic Chemistry, Institute of Chemical Technology, 166 28 Prague 6, Czech Republic
d Department of Medicinal Chemistry, Schering-Plough Corporation, Newhouse, ML1 5SH, Scotland, UK
e Department of Organic Chemistry, Charles University, 128 40, Prague 2, Czech Republic
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 June 2008
Received in revised form 19 August 2008
Accepted 27 August 2008
Available online 4 September 2008
Asymmetric allylation of aromatic aldehydes 1 with allyltrichlorosilane (2) can be catalyzed by new
terpene-derived bipyridine N,N0-dioxides 12–15 and an axially chiral biisoquinoline dioxide 17b with
good enantioselectivities. Dioxides have been found to be more reactive catalysts than their monooxide
counterparts.
Crown Copyright Ó 2008 Published by Elsevier Ltd. All rights reserved.
Dedicated to the memory of Dr. Andy Parkin
Keywords:
Enantioselective allylation
Allylsilane
Organocatalysis
Asymmetric catalysis
Pyridine N-oxides
1. Introduction
O
OH
*
Catalyst*
SiCl3
+
R
R
Asymmetric allylation of aldehydes 1 with allyl- and crotyl-tri-
chlorosilanes,1 catalyzed by chiral Lewis bases1,2 (Scheme 1), has
evolved into a robust methodology, allowing a simple and practical
access to homoallylic alcohols.3 Since the latter products are of
interest to the pharmaceutical and fine-chemicals industries as
basic building blocks for the construction of more complex
1
2
3
Scheme 1. Asymmetric allylation of aromatic aldehydes. For R, see Table 1.
molecules, further development, enhancing the catalyst efficiency,
and broadening of the scope of the reaction is desirable.
Chiral, pyridine-based N-oxides have emerged in the last few
years as powerful Lewis-basic catalysts for this transformation with
good to excellent enantioselectivities and with catalyst loading that
is unusually low in the organocatalyst realm. Thus, various C2-
symmetrical bipyridine N,N0-dioxides, such as 4–7 (Chart 1), have
been developed by several groups,4–7 including our own,8 and their
enantioselectivities were demonstrated with the aid of a portfolio of
aromatic aldehydes (with ꢀ90% ee for benzaldehyde; Table 1, entries
1–5). Simultaneously, we have shown that pyridine monooxides,
such as 8–11 (entries 6–11), can more than successfully compete
with the dioxides,8–12 and METHOX (10)11 can be regarded as the
current champion catalyst in terms of enantioselectivity, reactivity,
* Corresponding authors. Tel.: þ44 (0) 1509 222 569 (A.V.M.); tel.: þ44 (0) 141
330 4199; fax: þ44 (0) 141 330 4888 (P.K.).
E-mail addresses: a.malkov@lboro.ac.uk (A.V. Malkov), pavelk@chem.gla.ac.uk
ˇ
´
(P. Kocovsky).
y
Present address: Department of Chemistry, University of Loughborough, Lei-
cestershire LE11 3UT, UK.
z
Present address: ChiroBlock GmbH, Andresenstr. 1a, 06766 Wolfen, Germany.
Present address: Departamento de Productos Naturales, IQOG (CSIC), Madrid,
x
Spain.
{
Present address: Erasmus-Socrates exchange student from Charles University,
Prague, Czech Republic.
0040-4020/$ – see front matter Crown Copyright Ó 2008 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.08.084

11336
A.V. Malkov et al. / Tetrahedron 64 (2008) 11335–11348
Pyridine-type N-oxides as organocatalysts
Ph
HO
OH
+N
+N
O−
O−
R
+
N
+
+
N
+N
N
O−
−O
−O
O−
(S)-(−)-6a, R = Me
(S)-(+)-6b, R = CF3
(S)-(−)-4
(R)-(−)-5
R
R
+
N
+N
N+
O−
N
+
N
N
O−
−O
O−
R
R
(+)-9a, R = H
(−)-9b, R = Me
(−)-9c, R = Bu
(−)-9d, R = i-Pr
(+)-8a, R = H
(aR)-(+)-8b, R = Me
(aS)-(−)-8c, R = Me
(−)-7
OMe
OMe
+N
O−
OMe
OMe
+
N
−O
(R)-(+)-11
(+)-10
Chart 1. Pyridine-type N-oxides as organocatalysts.
New Pyridine-derived organocatalysts.
Table 1
Allylation of aldehydes RCHO (1) with 2 catalyzed by Lewis bases 4–11 (Scheme 1
and Chart 1)a
Entry Aldehyde
Catalyst
(mol %)
Solvent Temp Time Yield ee Configu
Ref
+N
N+
+N
N+
1 (R)
(ꢁC) (h) (%)
(%) ration of 3
−O O−
−O O−
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
(S)-(ꢂ)-4 (20) CH2Cl2 ꢂ78
(R)-(ꢂ)-5 (0.1) MeCN ꢂ45
(S)-(ꢂ)-6a (5) CH2Cl2 ꢂ78
(S)-(þ)-6b (5) CH2Cl2 ꢂ78
6
2.5
6
85 88 (R)-(þ)
95 84 (S)-(ꢂ)
87 74 (R)-(þ)
53 72 (R)-(þ)
18 41 (R)-(þ)
78 90 (S)-(ꢂ)
23 93 (S)-(ꢂ)
ꢃ95 96 (S)-(ꢂ)
60 87 (R)-(þ)
85 96 (R)-(þ)
70 16 (R)-(þ)
4
5
7
7
8
8
8
11
10
10
10
(+)-12
(+)-13
6
(ꢂ)-7 (10)
(þ)-8a (10)
(ꢂ)-9d (10)
(þ)-10 (5)
CH2Cl2 ꢂ90 48
CH2Cl2 ꢂ60 24
+N
N+
+N
CH2Cl2 ꢂ20 18
MeCN ꢂ40 18
−O O−
−O
9
(R)-(þ)-11 (5) CH2Cl2 ꢂ40
2
2
−O N+
R
R
10
11
4-CF3–C6H4 (R)-(þ)-11 (5) CH2Cl2 ꢂ40
4-MeO–C6H4 (R)-(þ)-11 (5) CH2Cl2 ꢂ40 12
(+)-14a, R = H
(+)-14b, R = Me
(−)-14c, R = Bu
(+)-14d, R = i-Pr
(−)-15a, R = H
(−)-15b, R = Me
(−)-15d, R = i-Pr
synthetic availability, and scope (entry 8). QUINOX (11) proved to be
rather more fastidious with respect to the aldehyde substrate, giving
very high enantioselectivities with electron-poor aldehydes (entry
10) but low with their electron-rich congeners (entry 11).10
R
R
+N
+N
O−
O−
O−
OMe
+N
2. Results and discussion
2.1. Catalyst design
R
(R)-(+)-16a, R = Me
(R)-(+)-16b, R = Ph
(R)-(+)-16c, R = 3,4,5-(MeO)3C6H2
(R)-(+)-16d, R = 2-furyl
(S)-(−)-17a, R = H
(R)-(+)-17b, R = Ph
(S)-(−)-17b, R = Ph
A comparison of the C2-symmetrical dioxide 7 with its mono-
oxide counterpart 8a (PINDOX) clearly shows the superiority of the
latter (41 vs 90% ee; Table 1, compare entries 5 and 6).8 On the other
hand, the non-terpene bipyridine dioxides 4 and 5 performed much
better than 7 (entries 1 and 2),4,5 exhibiting selectivities compa-
rable with 8a (entries 6 and 7). Since the relatively low level of
asymmetric induction in the case of 7 may, a priori, be associated
with its particular architecture, it was desirable to synthesize fur-
ther terpene-derived dioxides for comparison. To this end, we set
out to prepare the C1-symmetrical dioxide 12 (Chart 2) as a quino-
line analogue of the C2-symmetrical catalyst 7, the benzoquinoline
Chart 2. New pyridine-derived organocatalysts.
analogue 13 with an isomeric terpene unit, and a series of bipyr-
idine analogues with a phenyl or (a-pyridyl)phenyl pendants 14a–
d and 15a,b,d. This small library of catalyst candidates was
extended by the axially chiral monooxides 16a–d and dioxide 17b
(a derivative of the known dioxide 17a4 that can also be regarded as
an analogue of 55) for additional comparison.

A.V. Malkov et al. / Tetrahedron 64 (2008) 11335–11348
11337
a-pyridinio ketones 27–30, which in turn were obtained from the
X
corresponding methyl ketones 23–26 on iodination in pyridine at
110 ꢁC for 3–24 h (Scheme 3). Unlike with acetophenone and its
close congeners,13 the heteroaromatic Kro¨hnke salts 27–30 proved
to be more difficult to obtain in a pure state; nevertheless, the
crude materials were used as obtained without further purifica-
tion. These crude salts reacted with the terpenic enones 21/22 as
expected under the standard annulation conditions (AcONH4, pi-
peridine, n-BuOH, AcOH, 110 ꢁC, 1–2 days)13,17,18 to produce the
desired pyridine derivatives (þ)-31 (53%), (þ)-32 (53%), (þ)-33a
(47%),19 and (þ)-34a (36%), respectively. Under microwave con-
ditions, the annulation proceeded much faster but with little ef-
fect on the yield. Thus, for instance, 33a was obtained in 52% yield
by microwave heating at 190 ꢁC for 10 min, which differs mar-
ginally from the yield attained by traditional heating (47%).
The pyridinoterpene (þ)-33a was deprotonated with n-BuLi
(THF, ꢂ40 ꢁC, 3 h) in the ‘benzylic’ position and the resulting anion
was alkylated with alkyl iodides (THF, room temperature, over-
night) to afford the alkylated products (þ)-33b (39%), (þ)-33c
(−)-18, X = CH2
(+)-19, X = O
(+)-20
1. O3
1O2
Ac2O
2. NaNH2
HCO2(i-Am)
3. CH2O, K2CO3
O
O
(+)-21
(−)-22
Scheme 2. Synthesis of terpene precursors.
(45%), and (ꢂ)-33d (43%), respectively, in
a highly diaster-
eoselective fashion.20 It is pertinent to note that the latter depro-
tonation with n-BuLi proved superior to that using LDA8,19 in terms
of efficiency. Similarly, deprotonation of 34a, followed by alkyl-
ation, afforded the alkyl derivatives 34b (31%) and 34d (37%) with
a similarly high stereoselectivity. Oxidation of all these bipyridines
31, 32, 33a–d, and 34a,b,d with m-chloroperoxybenzoic acid
(2.2 equiv)8 in CH2Cl2 at room temperature for two days gave rise to
the desired dioxides (þ)-12 (86%), (þ)-13 (28%), (þ)-14a (28%),
(þ)-14b (44%), (ꢂ)-14c (47%), (þ)-14d (45%), (ꢂ)-15a (60%), (ꢂ)-15b
(42%), and (ꢂ)-15d (45%), respectively.
2.2. Catalyst synthesis
As in our previous work, enones (þ)-21 and (ꢂ)-22 were utilized
as the key building blocks for the terpene scaffold (Scheme 2).8–11,13
The former enone was obtained from (ꢂ)- -pinene (ꢂ)-18 in
b
a three-step procedure, including ozonolysis13,14 and Claisen con-
densation of the resulting nopinone (þ)-19, followed by a trans-
aldolization reaction with formaldehyde.13,15 Pinocarvone (ꢂ)-22
was obtained via the ene-reaction of (þ)- -pinene (þ)-20 with
a
singlet oxygen in the presence of acetic anhydride.8,13,16
The preparation of the starting heteroaryl ketones 23–25
(Scheme 4) requires a brief comment. Several methods were
attempted, including (a) the reaction of the corresponding nitrile
ArCN (e.g., 35) with MeMgI, followed by hydrolysis of the in situ-
formed imine;21 (b) addition of MeLi to the corresponding ester
ArCO2Me at low temperature;22 and (c) Claisen condensation of
ArCO2Et with AcOEt, followed by decarboxylation of the resulting
The enones (þ)-21 and (ꢂ)-22 were employed as Michael ac-
ceptors in the Kro¨hnke annulation17,18 with the easily enolizable
I−
N+
I2
pyridine
Ar
Ar
O
O
b
-keto ester ArCOCH2CO2Et,23 but the results were rather poor.
23, Ar = 2-quinolyl
27, Ar = 2-quinolyl
Finally, we settled for the reaction of the corresponding methyl
esters 37–39 with Me3Al in CH2Cl2 at ꢂ20 ꢁC,24 which gave the
respective methyl ketones 23 (88%), 24 (51%), and 25 (80%) con-
sistently in good yields. The required starting methyl ester 37 was
prepared by Fischer esterification25 of acid 36 (MeOH, H2SO4,
reflux; 88%), which in turn was obtained by hydrolysis of nitrile 35
(99%) under acidic conditions.26 The remaining methyl esters 38
and 39 are known compounds.27,28 The methyl ketone 26 was
obtained by the Suzuki–Miyaura coupling of 2-bromopyridine with
(3-acetyl)phenylboronic acid.29
24, Ar = benzoquinolyl
25, Ar = 6-Ph-(2-pyridyl)
26, Ar = 3-(2-pyridyl)-C6H4
28, Ar = benzoquinolyl
29, Ar = 6-Ph-(2-pyridyl)
30, Ar = 3-(2-pyridyl)-C6H4
AcONH4
O
O
Krohnke
annulation
(+)-21
(−)-22
(+)-13
(+)-14a
(−)-15a
MCPBA
Ar
N
N
N
1. HCl, H2O
reflux 2 d
2. MeOH, H+
reflux 6 h
(+)-31
MCPBA
(+)-12
(+)-32, Ar = benzoquinolyl
(+)-33a, Ar = 6-Ph-(2-pyridyl)
(+)-34a, Ar = 3-(2-pyridyl)-C6H4
RO
NC
N
N
O
35
36, R = H
37, R = Me
n-BuLi, R-I
MeO
O
Ar
Me3Al
-20 °C, 12 h
N
N
N
38, Ar = 2-quinolyl
39, Ar = 6-Ph-(2-pyridyl)
Ph
N
R
R
MCPBA
Me3Al
-20 °C, 12 h
N
O
(+)-33b, R = Me
(+)-33c, R = Bu
(−)-33d, R = i-Pr
(+)-34b, R = Me
(−)-34d, R = i-Pr
14b-d
15b,d
23 and 25
24
Scheme 3. Synthesis of new pyridine-derived organocatalysts.
Scheme 4. Synthesis of ketones 23–25.

11338
A.V. Malkov et al. / Tetrahedron 64 (2008) 11335–11348
The axially chiral tetrahydroisoquinoline-type catalyst candi-
(ꢄ)-17b (57%), accompanied by the corresponding monooxide
(20%). Racemic dioxide 17b resisted a number of attempts at clas-
sical resolution (including our favorite co-crystallization with
BINOL4a,10) and was eventually resolved by chiral HPLC. Attempted
synthesis of enantiopure 17b via a coupling of 17a (which in turn
can be prepared enantiomerically pure4) with PhBr, catalyzed by
(AcO)2Pd in the presence of Bu3P and HBF4,36 was unsuccessful.
An alternative synthesis of chloroisoquinoline 45 (Scheme 7),
a precursor to 17b, commenced with o-bromo-benzaldehyde (47)
that was first coupled with phenylacetylene under the standard
Sonogashira conditions, and the resulting aldehyde 48 (99%)37 was
converted into imine 49 on treatment with t-BuNH2 (94%).38 The
latter imine was then cyclized on heating with CuI (20 mol %) in DMF
to afford 3-phenylisoquinoline 50 (68%).39 The N-oxidation of the
latter product with m-CPBA gave rise to N-oxide 51 (75%),40 whose
treatment with POCl3 provided the 1-chloro derivative 45 (50%).
dates 16a–d (Scheme 5) were synthesized by using the asymmetric
[2þ2þ2] cyclotrimerization30 of diyne 40 with a series of nitriles,
catalyzed by the chiral cobalt complex (ꢂ)-(pS)-(
h
4-cycloocta-1,5-
diene)(
h
5-1-neomenthylindenyl)cobalt (ꢂ)-41 (1-2 mol %) under
irradiation with
a
high intensity visible-light lamp
(
l¼350–
500 nm) in THF at ꢂ20 ꢁC for 24–72 h as the key step. The tetra-
hydroquinolines (þ)-42a (86% yield, 93% ee),30a (þ)-42b (88% yield,
88% ee),30a (þ)-42c (64% yield, 91% ee),30b and (þ)-42d (81% yield,
91% ee)30b thus obtained were purified to high enantiopurity (>99%
ee) by recrystallization. Only (þ)-42c resisted the purification and
was used in its 91% enantiopurity. The absolute configuration of
(þ)-42b was established previously by X-ray crystallography to be
(R)30 and the configuration of the remaining members of this series
(42a,c,d) is assumed to be the same by analogy (as all of them are
dextrorotatory). The latter products were then oxidized with m-
chloroperoxybenzoic acid to afford the corresponding N-oxides 16a
(40%), 16b (35%), 16c (57%), and 16d (20%).
Ph
Br
Ph
(Ph3P)2PdCl2
CuI, Et3N
R
N
CHO
CHO
47
48
N
C R
hν, THF
OMe
OMe
t-BuNH2
Ph
Ph
40
(R)-(+)-42a, R = Me
CuI
(R)-(+)-42b, R = Ph
(R)-(+)-42c, R = 3,4,5-(MeO)3C6H2
(R)-(+)-42d, R = 2-furyl
Co
N
N
DMF
100 °C
(t-Bu)
50
49
41
MCPBA
MCPBA
Ph
Ph
(R)-(+)-16a−d
POCl3
+N
N
Scheme 5. Synthesis of axially chiral N-oxides 16.
O−
Cl
Finally, the synthesis of N,N0-dioxide 17b (Scheme 6) com-
menced with the annulation of benzonitrile to o-methyl-benza-
mide 43, mediated by an excess of n-butyllithium (5 equiv) in THF
(ꢂ50 ꢁC for 2 h, then at room temperature for 26 h), which afforded
isoquinolinone 44 (36%).31,32 Treatment of the latter product with
a mixture of POCl3 and PCl5 (neat) at 120 ꢁC for 2 h33 furnished
chloroisoquinoline 4532 (63%). Subsequent dimerization, mediated
by the in situ-generated (Ph3P)2NiCl2 and zinc in DMF at 50 ꢁC for
3 h,8,13,34 provided the biaryl derivative 46 (67%).35 The final oxi-
dation with m-chloroperoxybenzoic acid (10 equiv) in CH2Cl2 at
room temperature for 48 h resulted in the formation of dioxide
45
51
Scheme 7. An alternative synthesis of 45.
The absolute configuration of bisisoquinoline 17b can be tenta-
tively related to that of 17a, whose absolute configuration was un-
equivocally established by X-ray analysis of the molecular crystal
resulting from the co-crystallization of (ꢄ)-17a with (R)-(þ)-BINOL.4a
The levorotatoryenantiomer(S)-(ꢂ)-17a thus obtained exhibited[
a]
D
ꢂ180 (c 1.0, CHCl3). Chromatography of our (ꢄ)-17b on a chiral col-
umn afforded (ꢂ)-17b, exhibiting [ ꢂ184 (c 0.45, CHCl3), and
(þ)-17b with [ ]D þ178 (c 0.32, CHCl3), which correlates well with the
a]
D
a
optical rotation reported for (S)-17a. Moreover, the dextrorotatory
enantiomers of BINOL41 and its analogues, such as BINAM,41 NOBIN,41
3,30-diphenyl-BINOL,42 3-methoxycarbonyl-BINOL,41 and 3,30-(dime
thoxycarbonyl)BINOL41 are all (R)-configured. Therefore, it can be
tentatively concluded that the molecular architecture of (R)-1,10-
binaphthyl and (R)-1,10-bisisoquinolyl moieties with 2,20-oxygen
functions (i.e., diol or N,N0-dioxide) renders these derivatives dex-
trorotatory, unless other strongly contributing groups42 interfere.
Hence, the configuration of our bisisoquinoline can be assumed to be
(R)-(þ)-17b and (S)-(ꢂ)-17a. Further indirect evidence, stemming
from the sense of asymmetric induction of the allylation reaction,
catalyzed by 17b and 4–6, is discussed below.
n-BuLi
Me
NHMe
Ph
NH
N
C Ph
O
O
43
44
POCl3
PCl5
Ph
Ph
NiCl2, Zn
Ph3P, DMF
N
N
Ph
N
Cl
45
46
MCPBA
2.3. Allylation of aromatic aldehydes
We have shown previously that chiral, terpene-derived N,N0-
dioxides (e.g., 7) and N-monooxides (e.g., 8) with a flexible aryl–
aryl axis adopt a suitable conformation on coordinating the silicon
(+)-17b
Scheme 6. Synthesis of bisisoquinoline dioxide 17b.

A.V. Malkov et al. / Tetrahedron 64 (2008) 11335–11348
11339
Table 2
Allylation of aldehydes RCHO (1) with 2 catalyzed by Lewis bases 12, 14, 15, 16, and 17 (Scheme 1 and Chart 2)a
Entry
Aldehyde 1 (R)
Catalyst (mol %)
Solvent
Temp (ꢁC)
Time (h)
Conversion (%)b
ee (%)b
Configuration of 3c
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
(þ)-12a (10)
CH2Cl2
CH2Cl2
MeCN
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
MeCN
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
ꢂ60
40
18
18
18
18
18
18
18
12
18
18
18
12
18
18
18
18
18
18
18
18
18
18
18
2
ꢃ99
ꢃ99
ꢃ99
ꢃ99
19
ꢃ99
ꢃ99
ꢃ99
18
ꢃ99
ꢃ99
ꢃ99
87
36
26
31
25
42
4
40
56
34
43
23
31
10
23
12
2
(R)-(þ)
(R)-(þ)
(R)-(þ)
(R)-(þ)
(R)-(þ)
(S)-(ꢂ)
(S)-(ꢂ)
(S)-(ꢂ)
(S)-(ꢂ)
(S)-(ꢂ)
(S)-(ꢂ)
(S)-(ꢂ)
(R)-(þ)
(S)-(ꢂ)
(R)-(þ)
(R)-(þ)
(R)-(þ)
(S)-(ꢂ)
(S)-(ꢂ)
(S)-(ꢂ)
(S)-(ꢂ)
(S)-(ꢂ)
(S)-(ꢂ)
d
(þ)-12a (10)
(þ)-12a (10)
ꢂ60
ꢂ40
ꢂ40
ꢂ40
ꢂ40
ꢂ40
ꢂ90
ꢂ20
ꢂ20
ꢂ20
ꢂ20
ꢂ40
ꢂ20
ꢂ20
ꢂ20
ꢂ40
ꢂ40
ꢂ20
ꢂ40
ꢂ40
ꢂ40
23
(þ)-12a (10)
(þ)-13a (10)
(þ)-14a (10)
(þ)-14b (10)
(ꢂ)-14c (10)
9
(ꢂ)-14c (10)
10
12
13
14
15
16
17
18
19
20
21
22
23
24
25f
26
27
28
29
30
31
32
33
(ꢂ)-14c (10)
(ꢂ)-14c (10)
(ꢂ)-14c (10)
(ꢂ)-14c (10)
(ꢂ)-14d (10)
ꢃ99
(ꢂ)-15a (10)
83
(ꢂ)-15b (10)
87
85
<5
10
64
60
16
60
Ph
Ph
Ph
Ph
(ꢂ)-15d (10)
3
4
(R)-(þ)-16b (5)
(R)-(þ)-16ce (5)
(R)-(þ)-16ce (10)
(R)-(þ)-16ce (10)
(R)-(þ)-16ce (10)
(R)-(þ)-16de (10)
(R)-(þ)-17ae (10)
(R)-(þ)-17be (1)
(R)-(þ)-17be (1)
(S)-(ꢂ)-17be (1)
(R)-(þ)-17be (1)
(S)-(ꢂ)-17be (1)
(S)-(ꢂ)-17be (1)
(S)-(ꢂ)-17be (1)
(R)-(þ)-17be (1)
CHCl3
CHCl3
CHCl3
CHCl3
50d
48d
46d
8d
7
4-CF3–C6H4
4-MeO–C6H4
Ph
Ph
Ph
CHCl3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
85
52
77
81
69g
71
76g
51g
2
ꢂ40
ꢂ80
ꢂ80
ꢂ80
ꢂ80
ꢂ80
ꢂ80
ꢂ80
18
18
18
18
30
92
18
18
ꢃ99
ꢃ99
ꢃ99
ꢃ99
ꢃ99
99
(S)-(ꢂ)
(S)-(ꢂ)
(R)-(þ)
(S)-(ꢂ)
(R)-(þ)
(R)-(þ)
(R)-(þ)
(S)-(ꢂ)
Ph
4-MeC6H4
3,5-Me2C6H3
4-Cl–C6H4
4-CF3–C6H4
4-MeO–C6H4
3,4-(MeO)2C6H3
ꢃ99
ꢃ99
10
a
The reaction was carried out at 0.2 mmol scale with 1.4 equiv of allyltrichlorosilane and 1.0 equiv of diisopropylethylamine.
Determined by chiral HPLC or GC.
The configuration of the products 3 was established by the comparison of their optical rotations (measured in CHCl3) and their GC and HPLC retention times with the
b
c
literature data and with the behavior of authentic samples (Ref. 8).
d
Note that the enantiopurity of catalyst 16c was only 91% ee (corresponding to the enantiopurity of 42c; vide supra).
The absolute configuration is assumed in analogy (see the text) but not rigorously proven.
Ref. 4a.
e
f
g
The (S)-catalyst was about 90% enantiopure, which is reflected in the ee of the product compared to the (R)-enantiomer.
of the allylsilane 2;8 here, the configuration at the axis is thus
controlled by the chirality of the rest of the molecule in con-
junction with the conformational effects introduced by co-
ordination of the silicon. A similar scenario was expected to
operate with the new N,N0-dioxides 12–15. The latter derivatives,
lacking the C2 symmetry of 7 and having the chirality ‘‘concen-
trated’’ on one side of the molecule, proved to catalyze the ally-
lation of benzaldehyde (1) with AllylSiCl3 (2) efficiently with high
isolated yields of the homoallylic alcohol 3. However, the enan-
tioselectivity (Table 2, entries 1–18) turned out to be rather low
(ꢀ56% ee; entry 8), reflecting the behavior of dioxide 7 (41% ee;
Table 1, entry 5). Again, as shown previously,8 dichloromethane
proved to be the solvent of choice (Table 2; compare entry 10 with
12 and 13).
These experiments clearly demonstrated the superiority of N,N0-
dioxides 4–6, where the chiral axis is the only source of chirality in
the molecule, over those N,N0-dioxides, where the chiral terpene
moiety (12–15) is expected to exercise the enantiocontrol (compare
entries 1–4 in Table 1 with entries 1–18 in Table 2).
In view of the catalytic success of the axially chiral N-monooxide
QUINOX 11 (Table 1, entries 9 and 10),10 its analogues 16a–d with an
additional substituent R next to the N-oxide group, were in-
vestigated as the next step. However, these new derivatives proved
rather inefficient (ꢀ50% ee; Table 2, entries 19–24). Furthermore,
the reactions catalyzed by these N-monooxides were considerably
slower than those proceeding in the presence of N,N0-dioxides
(compare the yields in entries 1–18 vs 19–24 in Table 2). This
behavior indicates that chelation of the silicon atom of 2 between
the two oxygens of the catalysts enhances the nucleophilicity of the
allyl group considerably more than coordination to just one Lewis-
basic oxygen of the N-monooxide,43 unless other factors can con-
tribute to the stabilization of the transition state and lowering of
the activation energy.10b Furthermore, comparison of the efficiency
of QUINOX 11 with that of its analogues 6a,b7 and 16a–d indicates
that the bulky substituent next to the N–O group interferes with the
coordination of the silicon (vide infra).
Finally, the bis-isoquinoline N,N0-dioxide 17b can be regarded as
a hybrid between Nakajima’s moderately successful unsubstituted
analogue 17a (Table 2, entry 24) and Hayashi’s very efficient
bipyridine N,N0-dioxide 5 (Table 1, entry 2). Indeed, our dioxide 17b
exhibited excellent reactivity even at ꢂ80 ꢁC and 1 mol % loading.
The enantioselectivity was in the range of that reported by Hay-
ashi’s for dioxide 5, both for benzaldehyde (Table 2, entries 26 and
27), its methyl derivatives (entries 28 and 29), and electron-poor
congeners (entries 30 and 31). Interestingly, the electron-rich de-
rivatives of benzaldehyde turned out to give the products with poor
selectivity (entries 32 and 33), which reflects the behavior of
QUINOX 1110 (Table 1, entries 9–11).
The sense of asymmetric induction in the allylation catalyzed by
the axially chiral N,N0-dioxides 4–6 correlates well with that ob-
served for 17b: here, the (R)-configured dioxides induce the for-
mation of (S)-homoallylic alcohols (S)-(ꢂ)-3 [and (R)-(þ)-3 results
from the catalysis by (S)-dioxides] (Table 1, entries 1–4). Since
(þ)-17b promotes the formation of (S)-(ꢂ)-3 (Table 2, entries 26, 27,

11340
A.V. Malkov et al. / Tetrahedron 64 (2008) 11335–11348
and 29) and (ꢂ)-17b gives (R)-(þ)-2 (entries 28, 30, and 31), this
behavior can be used as another piece of evidence for the absolute
configuration of dioxide 17b as being (R)-(þ)-17b and (S)-(ꢂ)-17b.44
The striking difference in the reactivity and selectivity of N,N0-
dioxide and N-monooxide catalysts suggests that the two catalyst
types may operate via different mechanisms. In the case of bidentate
N,N0-dioxides, cationic transition state A (Scheme 8) can be envi-
sioned, in analogy with the mechanism proposed by Denmark for
his bis-phosphoramide activators.2 It has been demonstrated3–5,7,8
that the axial chirality of the catalyst plays a dominant role in con-
trolling the enantioselectivity. The axially chiral N,N0-dioxides 17
follow the general trend, exhibiting good levels of ee. For the flexible
dioxides 12–14, the chiral twist about the 2,20-bipyridine axis, which
plays the key role in the enantiodiscrimination event, is created on
chelation of the silicon and is influenced by the chirality of the
annulated terpene unit. Low to moderate enantioselectivities
obtained with catalysts 12–14 (Table 2, entries 1–15) suggest that
the remote terpene fragment is not capable of promoting selective
formation of only one of the possible atropoisomeric complexes. Our
recent studies on the mechanism of allylation catalyzed by the N-
monooxide QUINOX (11) revealed10b that the reaction proceeds via
an associative, single catalyst pathway, involving the neutral octa-
hedral silicon complex B. A highly crowded structure of the TS B
provides an excellent enantiocontrol in the allylation of aromatic
aldehydes, except for the electron-rich derivatives. However, the
latter transition state is likely to be sensitive to any variation in the
catalyst structure proximal to the coordinating center. To accom-
modate the increased steric demands created by the substituent
next to the N-oxide group, as in the case of N-oxides 16, one of the
chlorides is likely to dissociate from the silicon, generating the
cationic, trigonal bipyramidal complex C. Increased flexibility of C
may account for the observed drop in enantioselectivity for 16
compared to the unsubstituted 11. The low selectivity observed for
the allylation of the electron-rich aromatic aldehydes appears to be
a common feature of catalysis by 11, 16, and 17, and may result from
a change either in the rate liming step (RLS) or in the reaction
mechanism. In the case of QUINOX (11), operating via TS B, the
dramatic drop in enantioselectivity (from 96 to 16% ee, observed
with 4–CF3–C6H4CHO and 4–MeO–C6H4CHO, respectively) was at-
tributed to the shift in the RLS from precoordination of the aldehyde
to the C–C bond formation.10b Therefore, it might be tempting to
speculate about similar effects in the case of catalysts 16 and 17;
however, we currently do not have sufficient kinetic and computa-
tional data to create a full mechanistic picture.
reports4,5 on the axially chiral dioxides 4 and 5. The axially chiral
isoquinoline N-oxide 11 (QUINOX), known to be very efficient
(except for the electron-rich aromatic aldehydes),10 has been found
to have a scaffold that is very sensitive to any substitution in the
a-position to the N-oxide group, as the series of catalysts 16a–
d exhibited diminished selectivity and reaction rates. A study,
which aims at shedding light on the mechanistic issues of these
catalytic systems, is under way.
4. Experimental
4.1. General methods
All reactions were carried out under an inert atmosphere in an
oven-dried glassware unless otherwise stated. Room temperature
refers to ambient room temperature (18–20 ꢁC); 0 ꢁC refers to an ice
slush bath. Heated experiments were conducted using thermo-
statically controlled oil baths. Reactions were monitored by thin
layer chromatography (TLC) using aluminum backed silica gel 60
(F254) plates, visualized using UV254nm and potassium permanga-
nate, PMA, Dragendorff and ninhydrin dips as appropriate. Flash
chromatography was carried out routinely using 60 Å silica gel
(Fischer) unless otherwise stated. Melting points were determined
on a Kofler block and are uncorrected. Optical rotations were
recorded for CHCl3 solutions at 20 ꢁC unless otherwise indicated
with an error of <ꢄ0.1. The
10ꢂ1 deg cm2 gꢂ1. The NMR spectra were recorded on a 400 MHz
spectrometer. Chemical shifts are reported in units, parts per
[
a
]
D
values are given in
d
million (ppm) downfield from TMS. Coupling constants (J) are in
hertz (Hz) and are unadjusted; therefore, due to limits in resolu-
tion, in some cases there are small differences (<1 Hz) in the
measured J value of the same coupling constant determined from
different signals. Splitting patterns are designed as follows: s, sin-
glet; d, doublet; t, triplet; dd, doublet of doublets; dt, doublet of
triplets; td, triplet of doublets; ddd, doublet of doublet of doublets;
tt, triplet of triplets; sp, septet; m, multiplet; br, broad. Various 2D
techniques and DEPT experiments were used to establish the
structures and to assign the signals. The IR spectra were recorded
for a thin film between NaCl plates, or as a KBr disc. The mass
spectra (EI and/or CI) were measured on a dual sector mass spec-
trometer using direct inlet and the lowest temperature enabling
evaporation. Enantiomeric excess was determined by chiral GC
analysis (using a Hewlett Packard 6890 Series GC system, Hewlett
Packard 3395 integrator and Supelco
a-DEXÔ 120 fused capillary
column 30 mꢅ0.25 mmꢅ0.25 m film thickness) or by chiral HPLC
m
analysis (using a Hewlett Packard Agilent 1100 Series quaternary
pump, vacuum degasser, diode array detector, manual injector and
Hewlett Packard ChemStation and a Chiralcel OJ-H or Chiralpak IB
0.46 cmꢅ25 cm column) as stated. The chiral GC and HPLC methods
were calibrated with the corresponding racemates.
+
+
N
O
X
N
X
N
Cl
Si
O
Cl Cl
Si
Cl
O
N
H
H
H
O
O
Si
Cl
Cl−
Cl
O
Cl
O
Cl−
Ph
Ph
Ph
B
C
A
4.2. General method for the preparation of acetyl derivatives
23–2524
Scheme 8.
3. Conclusions
The reaction was performed on a 5.0–26.7 mmol scale. A 2.0 M
solution of Me3Al in hexanes (2.0 equiv) was added dropwise to
a stirred solution of the corresponding methyl esters 37–39
(1.0 equiv) in anhydrous CH2Cl2 (40 mL) at ꢂ78 ꢁC (or ꢂ85 ꢁC). The
reaction mixture was then allowed to warm over a 30 min period,
to ꢂ20 ꢁC and then stirred at this temperature for 12 h. The reaction
was quenched by addition of 10 M HCl (10–30 mL) at ꢂ20 ꢁC and
then left to stir at this temperature for 10 min before being warmed
to 0 ꢁC. It was further stirred for 30 min and then allowed to warm
to room temperature. The layers were separated and the aqueous
phase was extracted with CH2Cl2 (3ꢅ20 mL). The combined organic
extracts were dried over MgSO4 and the solvent was removed in
We have developed a set of monodentate and bidentate chiral
Lewis bases featuring a pyridine N-oxide fragment as the key
structural element. These compounds were employed as catalysts
in the asymmetric allylation of aromatic aldehydes with allyl tri-
chlorosilane (1þ2/3). Dioxides 12–15, whose chirality originates
from the annulated terpene unit, reached up to 56% ee on this re-
action (Table 2, entry 8). On the other hand, the C2-symmetrical
N,N0-dioxide 17b exhibited good enantioselectivity and high re-
activity even at ꢂ80 ꢁC and with catalyst loading as low as 1 mol %
(81% ee; Table 2, entry 27), which is in line with the earlier

A.V. Malkov et al. / Tetrahedron 64 (2008) 11335–11348
11341
vacuo to give the crude product, which was purified by chroma-
tography on a column of silica gel (15–100 g) with a mixture of
petroleum ether and ethyl acetate (5:1) to afford the pure ketones
23–25.
J¼8.8 Hz, 1H), 8.81 (t, J¼8.0 Hz, 1H), 9.11 (d, J¼5.6 Hz, 2H); 13C
NMR
d 66.5 (CH2), 117.9 (CH), 127.0 (CH), 127.8 (CH), 128.4 (CH),
129.6 (CH), 129.8 (C), 131.3 (CH), 138.3 (CH), 142.7 (CH), 145.7
(CH), 146.3 (C), 146.4 (CH), 150.4 (C), 191.5 (C); IR (KBr) 1711
(s) cmꢂ1
n
.
4.2.1. 2-Acetylquinoline (23)
Prepared from methyl 2-quinolylcarboxylate 38 (5.00 g, 26.7 mmol)
and 2.0 M Me3Al (26.7 mL, 53.5 mmol), which was added at ꢂ78 ꢁC.
After work up, product 23 (3.658 g, 88%) was obtained as an off
white solid, which was pure enough for the next step by 1H NMR
analysis. Mp 95–97 ꢁC (lit.23a gives 80–97 ꢁC); 1H NMR (CDCl3,
4.3.2. 1-(2-Benzo[h]quinolin-2-yl-2-oxo-ethyl)-pyridinium
iodide (28)
Prepared from ketone 24 (0.850 g, 3.8 mmol), iodine (1.073 g,
4.2 mmol), and pyridine (10 mL) at reflux for 24 h. The dark
brown solid product 28 was isolated in a mixture with pyridinium
iodide (1:1.2), as determined by 1H NMR analysis and was then
used in the next step without separation. 1H NMR (d6-DMSO,
400 MHz)
d
2.79 (s, 3H), 7.58 (t, J¼8.0 Hz, 1H), 7.72 (t, J¼8.4 Hz, 1H),
7.79 (d, J¼8.0 Hz, 1H), 8.05 (d, J¼8.4 Hz, 1H), 8.13 (d, J¼8.8 Hz, 1H),
8.18 (d, J¼8.4 Hz,1H), consistent with the literature data;23 13C NMR
400 MHz)
d 6.94 (s, 2H), 7.97–8.13 (m, 2H), 8.05–8.10 (m, 2H), 8.23
d
24.6 (CH3), 116.9 (CH), 126.6 (CH), 127.5 (CH), 128.5 (C), 129.0 (CH),
(t, J¼8.8 Hz, 1H), 8.32–8.37 (m, 1H), 8.61 (t, J¼7.6 Hz, 2H), 8.76–
129.5 (CH), 135.8 (CH), 146.2 (C), 152.1 (C), 199.7 (C); IR (KBr)
(s) cmꢂ1
n 1695
8.82 (m, 1H), 8.96 (t, J¼6.4 Hz, 2H), 9.15 (d, J¼5.2 Hz, 2H); 13C NMR
.
d 66.8 (CH2), 119.2 (CH), 124.0 (CH), 125.4 (CH), 126.8 (CH), 127.8
(CH), 127.9 (CH), 128.5 (CH), 129.0 (C), 129.4 (CH), 130.3 (C), 130.8
(CH), 133.6 (C), 138.0 (CH), 143.2 (CH), 144.5 (C), 145.0 (CH), 146.4
4.2.2. 2-Acetyl-1-benzo[h]quinoline (24)24
Prepared from methyl benzo[h]quinoline-2-carboxylate 37
(2.000 g, 8.4 mmol) and 2.0 M Me3Al (8.43 mL, 16.9 mmol), which
was added at ꢂ85 ꢁC. Purification of the crude product furnished
ketone 24 (0.986 g, 51%) as a pale brown solid. Mp 116–118 ꢁC; 1H
(CH), 148.8 (C), 191.5 (C); IR (KBr) n .
1703 (s) cmꢂ1
4.3.3. 1-[2-Oxo-2-(6-phenyl-pyridin-2-yl)-ethyl]-pyridinium
iodide (29)
NMR (CDCl3, 400 MHz)
d
2.94 (s, 3H), 7.62 (d, J¼8.8 Hz, 1H), 7.63–
Prepared from ketone 25 (0.750 g, 3.8 mmol), iodine (1.063 g,
4.2 mmol), and pyridine (10 mL) at reflux for 24 h. The dark brown
solid product 29 was isolated in a mixture with pyridinium iodide
(1:2), as determined by 1H NMR analysis and it was then used in
the next step without separation. 1H NMR (d6-DMSO, 400 MHz)
7.72 (m, 2H), 7.81 (d, J¼8.8 Hz, 1H), 7.85 (d, J¼8.4 Hz, 1H), 8.15 (s,
2H), 9.27 (d, J¼8.0 Hz, 1H); 13C NMR
d 25.84 (CH3), 118.9 (CH), 124.5
(CH), 125.0 (CH), 127.5 (CH), 128.0 (CH), 128.39 (C), 128.7 (CH), 130.1
(CH), 131.6 (C), 133.7 (C), 136.6 (CH), 145.4 (C),151.6 (C), 200.8 (C); IR
(Golden Gate)
n
1687 (s) cmꢂ1; HRMS (EI) 221.0842 (C15H11NO re-
d
6.72 (s, 2H), 8.05 (d, J¼7.6 Hz, 1H), 8.11 (t, J¼6.8 Hz, 2H), 8.26 (t,
quires 221.0841).
J¼8.0 Hz, 1H), 8.30–8.33 (m, 3H), 8.45 (d, J¼8.0 Hz, 1H), 8.64 (t,
J¼8.0 Hz, 2H), 8.79 (t, J¼7.6 Hz, 1H), 9.07 (d, J¼5.6 Hz, 2H); 13C
4.2.3. 1-Acetyl-6-phenylpyridine (25)19,45
NMR d 66.75 (CH2), 120.5 (CH), 123.7 (CH), 125.2 (C), 126.9 (CH),
Prepared from methyl 6-phenylpyridine-2-carboxylate 39
(1.000 g, 5.0 mmol) and 2.0 M Me3Al (5.0 mL, 10.0 mmol), which
was added at ꢂ85 ꢁC. Purification of the crude product was gave
ketone 25 (784 mg, 80%) as a yellowish solid. Mp 59–61 ꢁC (lit.45
127.1 (CH), 127.8 (CH), 129.0 (CH), 130.1 (CH), 139.3 (CH), 142.6
(CH), 145.8 (CH), 146.3 (CH), 150.4 (C), 155.8 (C), 191.6 (C); IR (KBr)
n
1707 (s) cmꢂ1
.
gives 75–76 ꢁC); 1H NMR (CDCl3, 400 MHz)
d
2.75 (s, 3H), 7.37–7.46
(m, 3H), 7.78–7.85 (m, 2H), 7.91 (dd, J¼7.2,1.6 Hz,1H), 8.01–8.04 (m,
2H); 13C NMR
25.9 (CH3), 119.8 (CH), 123.5 (CH), 126.9 (2ꢅCH),
4.3.4. 1-{2-Oxo-2-[30-(200-pyridinyl)phenyl]ethyl}pyridinium
iodide (30)
d
Prepared from ketone 2629 (3.58 g, 89%). 1H NMR (400 MHz, d6-
128.9 (2ꢅCH), 129.5 (CH), 137.7 (CH), 138.4 (C), 153.4 (C), 156.5 (C),
DMSO)
d
6.63 (s, 2H, 1-H), 7.48 (dd, J¼7.2, 5.1 Hz, 1H, 500-H), 7.81 (t,
200.7 (C); IR (KBr)
requires 197.0841).
n
1693 (s) cmꢂ1; HRMS (EI) 197.0842 (C13H11NO
J¼7.8 Hz, 1H, 50-H), 8.02 (t, J¼7.2 Hz, 1H, 400-H), 8.13 (s, 1H, 20-H),
8.16 (d, J¼7.8 Hz, 1H, 40-H), 8.32 (t, J¼7.0 Hz, 2H, 3%-H, 5%-H), 8.48
(d, J¼7.8 Hz, 1H, 60-H), 8.74–8.80 (m, 3H, 300-H, 600-H, 4%-H), 9.05 (d,
4.3. General procedure for the preparation of Krohnke
J¼7.0 Hz, 2H, 2%-H, 6%-H); 13C NMR (100 MHz, d6-DMSO)
d 66.3
¨
salts17,19 27–30
(CH2-1), 120.8 (CH-40), 123.4 (CH-500), 126.1 (CH-300), 127.8 (2ꢅCH-
3%,5%), 128.7 (CH-20), 129.7 (CH-50), 132.3 (C-60), 134.1 (C-10), 138.0
(CH-400), 138.9 (C-30), 146.1 (2ꢅCH-2%,6%), 146.3 (CH-4%), 149.3
A solution of the respective substituted acetophenone 23–26
(10 mmol, 1.0 equiv) and iodine (2.53 g, 10 mmol, 1.0 equiv) in
pyridine (6 mL) was refluxed overnight. The reaction mixture was
then cooled to room temperature, inducing the precipitation of
a dark solid, which was filtered off and washed with ether
(3ꢅ20 mL). In some experiments, the mixture was concentrated by
evaporation of the pyridine in vacuo to facilitate the precipitation
prior to the washing with ether. The remaining solid was then
stirred overnight in ether (20 mL) and the salts 27–30 were then
isolated by filtration; this material was of sufficient purity for the
subsequent Kro¨hnke annulation.
(CH-600), 154.1 (C-200), 190.5 (C]O-2); MS (FAB) m/z (%) 275 (Mꢆþ
,
82), 241 (33), 136 (37), 122 (100), 101 (82), 82 (75); HRMS (FAB)
275.1181 (C18H15N2O requires 275.1184).
17,19
¨
4.4. General method for the Krohnke annulation
A mixture of enone (þ)-21 or (ꢂ)-22 (7.0 mmol, 1.00 equiv), the
Kro¨hnke salts 27–30 (7.1 mmol, 1.1 equiv), AcONH4 (9.0 g), and
piperidine (7.1 mmol, 1.1 equiv) in n-butanol (30 mL) and acetic
acid (10 mL), was heated at 110 ꢁC for 6 hdtwo days. After this
time, the reaction mixture was cooled to room temperature, di-
luted with water (25 mL), made neutral by addition of an aqueous
solution of sodium hydroxide (2 M), and extracted with ethyl ac-
etate (3ꢅ50 mL). The organic phase was successively washed with
water (3ꢅ50 mL) and brine (50 mL) and dried over MgSO4. The
solvent was removed under vacuum and the crude product was
purified by flash chromatography on silica gel (20 g) using a mix-
ture of petroleum ether and ethyl acetate (3:1) to afford pure
product.
4.3.1. 1-(2-Oxo-2-quinolin-2-yl-ethyl)-pyridinium iodide (27)
Prepared from ketone 23 (1.200 g, 7.0 mmol), iodine (1.908 g,
7.5 mmol), and pyridine (15 mL) at reflux for 3 h. The dark brown
solid product 27 was isolated in a mixture with pyridinium iodide
(1:2), as determined by 1H NMR analysis and was then used in
the next step without separation. 1H NMR (d6-DMSO, 400 MHz)
d
6.72 (s, 2H), 7.90–8.10 (m, 2H), 8.18 (d, J¼8.4 Hz, 1H), 8.23 (d,
J¼8.0 Hz, 1H), 8.28 (d, J¼8.4 Hz, 1H), 8.36 (t, J¼8.0 Hz, 2H), 8.75 (d,

11342
A.V. Malkov et al. / Tetrahedron 64 (2008) 11335–11348
4.4.1. (1R,9R)-(þ)-10,10-Dimethyl-4-(quinolin-2-yl)-3-aza-
tricyclo[7.1.1.02,7]undeca-2,4,6-triene (þ)-(31)
1H, 400-H), 7.74 (dt, J¼7.4, 1.0 Hz, 1H, 300-H), 7.97 (ddd, J¼7.8, 2.8,1.6 Hz,
1H, 60-H), 8.00 (ddd, J¼7.8, 2.8, 1.6 Hz, 1H, 40-H), 8.59 (t, J¼1.6 Hz, 1H,
20-H), 8.64 (ddd, J¼4.8, 1.8, 1.0 Hz, 1H, 600-H); 13C NMR (100 MHz,
Prepared by using 1-(2-oxo-2-quinolin-2-yl-ethyl)-pyridinium
iodide 27 (330 mg, 0.88 mmol), enone (þ)-21 (106 mg,
0.704 mmol), piperidine (66 mg, 0.77 mmol), and ammonium ac-
etate (3.000 g). Purification of the crude product afforded pure
CDCl3)d21.0(CH3),25.8(CH3),31.7(CH2-11), 36.5(CH2-8),39.2(C-10),
39.9 (CH-9), 45.9 (CH-1), 117.0 (CH-3), 120.3 (CH-300), 121.8 (CH-500),
125.0 (CH-20),126.5 (CH-60),127.0 (CH-40),128.8 (CH-50),133.2 (CH-4),
136.3 (CH-400), 139.4 (C-2), 140.2 (2ꢅC-10, 30), 149.3 (CH-600), 154.1 (C-
200), 156.5 (C-5), 157.0 (C-7); MS (EI) m/z (%) 326 (Mꢆþ, 100), 283 (66);
HRMS (EI) 326.1780 (C23H22N2 requires 326.1783).
(þ)-31 (141 mg, 53%) as a yellow, amorphous solid. [
a
]
þ28.7 (c
D
1.0, CHCl3); 1H NMR (CDCl3, 400 MHz)
d
0.65 (s, 3H), 1.32 (d,
J¼9.7 Hz, 1H), 1.39 (s, 3H), 2.35–2.38 (m, 1H), 2.75–2.80 (m, 2H),
2.96 (s, 1H), 3.09 (t, J¼5.6 Hz, 1H), 7.47 (t, J¼7.1 Hz, 1H), 7.54
(d, J¼7.8 Hz, 1H), 7.66 (t, J¼7.0 Hz, 1H), 7.77 (d, J¼8.1 Hz, 1H), 8.10 (d,
J¼8.5 Hz, 1H), 8.18 (d, J¼8.7 Hz, 1H), 8.34 (d, J¼7.8 Hz, 1H), 8.48 (d,
4.5. General procedure for the alkylation of bipyridines
33a and 34a
J¼8.6 Hz, 1H); 13C NMR
d 21.3 (CH3), 26.1 (CH3), 30.9 (CH2), 31.4
(CH2), 39.2 (C), 40.2 (CH), 50.6 (CH), 119.2 (CH), 119.6 (CH), 126.4
(CH), 127.6 (CH), 128.1 (C), 129.4 (CH), 129.8 (CH), 131.1 (C), 136.1
(CH), 136.6 (CH), 148.0 (C), 152.3 (C), 156.9 (C), 165.9 (C); HRMS (EI)
300.1624 (C21H20N2 requires 300.1626).
The reaction was performed on a 1.6–3.3 mmol scale. A 2.5 M
solution of n-BuLi in hexanes (1.7 equiv) was added dropwise to
a solution of the pyridine derivative (þ)-33a19 or (þ)-34a (1.0 equiv)
in THF (5 mL) at ꢂ40 ꢁC, turning the solution dark red. The stirring
wascontinued for3 handthena solutionofalkyl halide(1.7 equiv)in
THF(2 mL)was added dropwise andthe reactionmixturewasstirred
at room temperature overnight. Water (10 mL) was then added and
the aqueous layer was extracted with CH2Cl2 (3ꢅ10 mL). The com-
bined organic layers were dried with MgSO4 and the solvent was
removed in vacuo to give the crude product, which was purified by
column chromatography on a column of silica gel (2 g) using a mix-
ture of petroleum ether and ethyl acetate (24:1) to give the alkylated
product. An alternative procedure employed LDA instead of n-BuLi.19
4.4.2. (1S,9S)-(þ)-10,10-Dimethyl-5-(20-benzo[h]quinolinyl)-6-
aza-tricyclo[7.1.1.02,7]undeca-2(7),3,5-triene (þ)-(32)
Prepared by using 1-(2-benzo[h]quinolin-2-yl-2-oxo-ethyl)-
pyridinium iodide 28 (900 mg, 2.11 mmol), enone (þ)-22 (253 mg,
1.7 mmol), piperidine (158 mg, 1.9 mmol), and ammonium acetate
(4.0 g). Purification of the crude product furnished product (þ)-32
(392 mg, 53%) as a yellow solid. Mp 146–148 ꢁC; [
a
]
þ26.0 (c 1.0,
D
CHCl3); 1H NMR (CDCl3, 400 MHz)
d
0.64 (s, 3H), 1.29 (d, J¼9.6 Hz,
1H), 1.36 (s, 3H), 2.33–2.37 (m, 1H), 2.63–2.68 (m, 1H), 2.79 (t,
J¼5.6 Hz,1H), 3.18 (d, J¼2.8 Hz, 2H), 7.36 (d, J¼8.0 Hz,1H), 7.59–7.72
(m, 4H), 7.83 (d, J¼8.0 Hz, 1H), 8.19 (d, J¼8.4 Hz, 1H), 8.50 (d,
J¼8.0 Hz, 1H), 8.62 (d, J¼8.4 Hz, 1H), 9.41 (d, J¼8.0 Hz, 1H); 13C NMR
4.5.1. (1S,8R,9S)-(þ)-8,10,10-Trimethyl-5-(30-phenyl-phenyl)-6-
aza-tricyclo[7.1.1.02,7]undeca-2(7),3,5-triene (þ)-(33b)
Prepared from bipyridine (þ)-33a19 (100 mg, 0.31 mmol),
n-BuLi (2.5 M in hexanes) (0.20 mL, 0.53 mmol), and methyl iodide
(75 mg, 0.53 mmol). Purification of the crude mixture afforded
d
21.4 (CH3), 26.1 (CH3), 32.0 (CH2), 36.8 (CH2), 39.6 (C), 40.3 (CH),
46.6 (CH), 118.7 (CH), 119.3 (CH), 124.6 (CH), 125.4 (CH), 126.1 (C),
126.9 (CH), 127.6 (CH), 127.8 (CH), 128.1 (CH), 131.8 (C), 133.8 (C),
134.0 (CH), 136.5 (CH), 142.6 (C), 145.9 (C), 154.0 (C), 155.2 (C), 156.4
(C); HRMS (EI) 350.1785 (C25H22N2 requires 350.1783).
(þ)-33b (41 mg, 39%) as a clear oil. [
a
]
þ24.0 (c 1.0, CHCl3); 1H
D
NMR (CDCl3, 400 MHz)
d
0.65 (s, 3H), 1.29 (d, J¼10.0 Hz, 1H), 1.43 (s,
3H), 1.42 (d, J¼7.2 Hz, 3H), 2.13 (dt, J¼6.0, 2.4 Hz, 1H), 2.48–2.54 (m,
1H), 2.82 (t, J¼5.6 Hz, 1H), 3.17–3.22 (m, 1H), 7.27 (d, J¼7.6 Hz, 1H),
7.35 (d, J¼7.2 Hz, 1H), 7.41 (t, J¼6.8 Hz, 2H), 7.66 (d, J¼7.2 Hz,
1H), 7.79 (t, J¼7.6 Hz, 1H), 8.09 (d, J¼7.2 Hz, 2H), 8.24 (d, J¼8.0 Hz,
4.4.3. (1S,9S)-(þ)-10,10-Dimethyl-5-(30-phenyl-phenyl)-6-aza-
tricyclo[7.1.1.02,7]undeca-2(7),3,5-triene (þ)-(33a)
Prepared
from
1-[2-oxo-2-(6-phenylpyridin-2-yl)-ethyl]-
1H), 8.30 (d, J¼8.8 Hz, 1H); 13C NMR
d 18.3 (CH3), 21.0 (CH3), 22.6
pyridinium iodide 29 (350 mg, 0.88 mmol), enone (ꢂ)-22 (118 mg,
0.80 mmol), piperidine (74 mg, 0.88 mmol), and ammonium ace-
tate (2.00 g). Purification of the crude product furnish the pure
product (þ)-33a as a whitish solid (136 mg, 47%). Mp 132–134 ꢁC;
(CH3), 26.4 (CH2), 38.9 (CH), 41.5 (C), 46.8 (CH), 47.2 (CH),118.0 (CH),
119.1 (CH),119.6 (CH),126.9 (2ꢅCH),128.7 (2ꢅCH),128.9 (CH),133.5
(CH), 137.5 (CH), 139.6 (C), 142.2 (C), 153.5 (C), 156.2 (C), 156.5 (C),
160.1 (C); HRMS (EI) 340.1937 (C24H24N2 requires 340.1939).
[
a
]
þ38.6 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz)
d 0.61 (s, 3H),
D
1.26 (d, J¼9.6 Hz, 1H), 1.35 (s, 3H), 2.31–2.35 (m, 1H), 2.61–2.66 (m,
1H), 2.76 (t, J¼5.6 Hz, 1H), 3.13 (d, J¼2.8 Hz, 2H), 7.29 (d, J¼7.6 Hz,
1H), 7.33–7.36 (m, 1H), 7.44 (t, J¼7.6 Hz, 2H), 7.66 (d, J¼7.6 Hz, 1H),
7.79 (t, J¼8.0 Hz, 1H), 8.09 (d, J¼7.2 Hz, 2H), 8.24 (d, J¼7.6 Hz, 1H),
4.5.2. (1S,8R,9S)-(þ)-8-Butyl-10,10-dimethyl-5-(30-phenyl-
phenyl)-6-aza-tricyclo[7.1.1.02,7]undeca-2(7),3,5-triene (þ)-(33c)
Prepared from bipyridine (þ)-33a19 (100 mg, 0.30 mmol),
n-BuLi (2.5 M in hexanes) (0.20 mL, 0.53 mmol), and n-butyl iodide
(98 mg, 0.53 mmol). Purification of the crude mixture furnished
8.28 (d, J¼8.0 Hz, 1H); 13C NMR
d 21.4 (CH3), 26.1 (CH3), 32.0 (CH2),
36.8 (CH2), 39.6 (C), 40.3 (CH), 46.5 (CH), 118.2 (CH), 119.1 (CH),
119.7 (CH), 127.0 (2ꢅCH), 127.2 (C), 128.7 (2ꢅCH), 128.9 (CH), 133.8
(CH), 137.6 (CH), 139.6 (C), 142.3 (C), 153.8 (C), 156.3 (C), 156.4 (C);
HRMS (EI) 326.1784 (C23H22N2 requires 326.1783) in accordance
with the literature,19 which however does not give the optical ro-
tation, although presumably the same enantiomer was obtained.
(þ)-33c (52 mg, 45%) as a clear oil. [
a
]
D þ8.0 (c 1.0, CHCl3); 1H NMR
(CDCl3, 400 MHz)
d
0.58 (s, 3H), 0.92 (t, J¼6.8 Hz, 3H), 1.27 (d,
J¼9.6 Hz, 1H), 1.36 (s, 3H), 1.43–1.47 (m, 5H), 2.25–2.34 (m, 2H),
2.45–2.51 (m, 1H), 2.74 (t, J¼5.2 Hz, 1H), 2.97–3.00 (m, 1H), 7.25
(d, J¼7.6 Hz, 1H), 7.36 (t, J¼7.2 Hz, 1H), 7.43 (t, J¼7.6 Hz, 2H), 7.65 (d,
J¼7.6 Hz, 1H), 7.79 (t, J¼7.6 Hz, 1H), 8.08 (d, J¼8.0 Hz, 2H), 8.23 (d,
J¼7.6 Hz, 1H), 8.34 (d, J¼7.6 Hz, 1H); 13C NMR
d 14.3 (CH3), 21.0
4.4.4. (1S,9S)-(þ)-10,10-Dimethyl-5-[30-(pyridin-200-yl)phenyl]-6-
(CH3), 23.1 (CH2), 26.5 (CH3), 28.5 (CH2), 30.2 (CH2), 32.4 (CH2), 41.2
(C), 43.4 (CH), 44.3 (CH), 47.0 (CH), 118.0 (CH),119.1 (CH), 119.6 (CH),
127.0 (2ꢅCH), 128.7 (2ꢅCH), 128.9 (CH), 133.5 (CH), 137.6 (CH),
139.6 (C), 142.2 (C), 153.4 (C), 156.2 (C), 156.6 (C), 159.8 (C); HRMS
(EI) 382.2406 (C27H30N2 requires 382.2409).
aza-tricyclo[7.1.1.02,7]undeca-2(7),3,5-triene (þ)-(34a)
18
Prepared from 30 and (ꢂ)-22 (820 mg, 36%): foam. [
a
]
þ58.7 (c
D
1.0, CHCl3); IR (NaCl)
n 2936 (m, C–H), 1587 (m, C]Car), 1466 (m,
C]Car), 1437 (m, C]Car), 761 (s, C–Har) cmꢂ1; 1H NMR (400 MHz,
CDCl3)
d
0.63 (s, 3H, CH3C), 1.24 (d, J¼9.5 Hz, 1H, 11-H), 1.33 (s, 3H,
0
CH3 C), 2.32 (tt, J¼5.8, 2.8 Hz, 1H, 9-H), 2.61 (dt, J¼9.5, 5.8 Hz, 1H, 11-
H0), 2.70 (t, J¼5.8 Hz, 1H, 1-H), 3.16 (d, J¼2.8 Hz, 2H, 8-H), 7.11 (ddd,
J¼7.4, 4.8, 1.0 Hz, 1H, 500-H), 7.18 (d, J¼7.8 Hz, 1H, 4-H), 7.44 (d,
J¼7.8 Hz, 1H, 3-H), 7.49 (t, J¼7.8 Hz, 1H, 50-H), 7.62 (td, J¼7.4, 1.8 Hz,
4.5.3. (1S,8R,9S)-(ꢂ)-10,10-Dimethyl-8-isopropyl-5-(30-phenyl-
phenyl)-6-aza-tricyclo[7.1.1.02,7]undeca-2(7),3,5-triene (ꢂ)-(33d)
Prepared from bipyridine (þ)-33a19 (50 mg, 0.16 mmol), n-BuLi
(2.5 M in hexanes) (0.11 mL, 0.27 mmol), and isopropyl iodide

A.V. Malkov et al. / Tetrahedron 64 (2008) 11335–11348
11343
(43 mg, 0.27 mmol). Purification of the crude mixture gave (ꢂ)-33d
solution of the bipyridine derivatives 31, 32, 33a–d, or 34a,b,d
(0.15 mmol, 1.0 equiv) in CH2Cl2 (4 mL). The mixture was then
allowed to warm up to room temperature and stirred overnight.
The mixture was washed with an aqueous solution of NaHCO3 (10%;
5 mL) and dried over MgSO4. The solvent was removed under
vacuum and the residue was purified by chromatography on silica
gel (10 g) using a mixture of petroleum ether and ethyl acetate (5:1)
to elute the unreacted starting material, followed by ethyl acetate,
to give the pure product.
(24 mg, 43%) as a clear oil. [
a
]
D ꢂ31.3 (c 1.0, CHCl3); 1H NMR (CDCl3,
400 MHz)
d
0.54 (s, 3H), 0.81 (d, J¼6.8 Hz, 3H),1.17 (d, J¼6.8 Hz, 3H),
1.35 (s, 3H), 1.40 (d, J¼9.6 Hz, 1H), 2.34 (dt, J¼6.0, 2.0 Hz, 1H), 2.50–
2.55 (m, 1H), 2.68 (t, J¼5.8 Hz, 1H), 2.78–2.83 (m, 1H), 2.91 (dd,
J¼4.4, 2.0 Hz, 1H), 7.28 (d, J¼7.6 Hz, 1H), 7.37 (d, J¼8.8 Hz, 1H), 7.45
(t, J¼7.6 Hz, 2H), 7.66 (d, J¼7.6 Hz, 1H), 7.81 (t, J¼7.6 Hz, 1H), 8.10 (d,
J¼8.0 Hz, 2H), 8.27 (d, J¼8.0 Hz, 1H), 8.34 (d, J¼7.6 Hz, 1H); 13C NMR
d
20.3 (CH3), 21.1 (CH3), 22.4 (CH3), 26.4 (CH3), 29.4 (CH2), 30.5 (CH),
41.5 (CH), 42.0 (C), 46.8 (CH), 49.2 (CH), 117.9 (CH), 119.1 (CH), 119.6
(CH),126.9 (2ꢅCH),128.7 (2ꢅCH),128.9 (CH),133.6 (CH),137.5 (CH),
139.6 (C), 142.7 (C), 153.2 (C), 156.2 (C), 156.7 (C), 158.7 (C); HRMS
(EI) 368.2255 (C26H28N2 requires 368.2252).
4.6.1. (1R,9R)-(þ)-10,10-Dimethyl-4-(quinolin-2-yl)-3-aza-
tricyclo[7.1.1.02,7]undeca-2,4,6-triene N,N0-dioxide (þ)-(12)
Prepared from bipyridine (þ)-31 (150 mg, 0.5 mmol) and m-
CPBA (190 mg, 1.1 mmol). Purification of the crude product afforded
the dioxide (þ)-12 (142 g, 86%) as a pale yellow solid. Mp 202–
4.5.4. (1S,8R,9S)-(þ)-8,10,10-Trimethyl-8-isopropyl-5-[30-(pyridin-
200-yl)phenyl]-6-aza-tricyclo[7.1.1.02,7]undeca-2(7),3,5-triene
(þ)-(34b)
204 ꢁC; [
a]
D þ17.3 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz)
d 0.74 (s,
3H), 1.29 (d, J¼10.0 Hz, 1H), 1.40 (s, 3H), 2.27–2.28 (m, 1H), 2.68–
2.73 (m, 1H), 2.99 (s, 2H), 4.04 (t, J¼6.0 Hz, 1H), 7.10 (d, J¼8.0 Hz,
1H), 7.44 (d, J¼8.0 Hz, 1H), 7.56 (d, J¼8.8 Hz, 1H), 7.61 (t, J¼7.6 Hz,
1H), 7.66–7.71 (m, 2H), 7.82 (d, J¼8.0 Hz, 1H), 8.75 (d, J¼8.8 Hz, 1H);
Prepared by alkylation of (þ)-34a; purification afforded (þ)-34b
23
(64 mg, 31%). [
a]
þ7.1 (c 1.0, CH2Cl2); IR (NaCl)
n 2926 (m, C–H),
D
1637 (m, C]Car), 1585 (m, C]Car), 1460 (m, C]Car), 773 (s, C–
Har) cmꢂ1
;
1H NMR (400 MHz, CD0Cl3)
d
0.61 (s, 3H, CH3C), 1.27 (d,
13C NMR
d 21.8 (CH3), 26.2 (CH3), 30.7 (CH2), 32.1 (CH2), 39.6 (C),
J¼9.8 Hz, 1H, 11-H), 1.35 (s, 3H, CH3 C), 1.41 (d, J¼7.1 Hz, 3H, CH3CH),
2.10 (td, J¼5.7, 2.5 Hz, 1H, 9-H), 2.50 (dt, J¼9.8, 5.7 Hz, 1H, 9-H0),
2.71 (t, J¼5.7 Hz,1H,1-H), 3.20 (qd, J¼7.1, 2.5 Hz,1H, 8-H), 7.15 (ddd,
J¼7.6, 4.8, 1.1 Hz, 1H, 500-H), 7.18 (d, J¼7.8 Hz, 1H, 4-H), 7.44 (d,
J¼7.8 Hz, 1H, 3-H), 7.48 (t, J¼7.7 Hz, 1H, 50-H), 7.68 (td, J¼7.6, 1.8 Hz,
1H, 400-H), 7.75 (dt, J¼7.6, 1.1 Hz, 1H, 300-H), 7.93 (ddd, J¼7.7, 1.7,
1.2 Hz, 1H, 60-H), 8.02 (ddd, J¼7.7, 1.7, 1.2 Hz, 1H, 40-H), 8.53 (t,
J¼1.7 Hz, 1H, 20-H), 8.64 (ddd, J¼4.8, 1.8, 1.1 Hz, 1H, 600-H); 13C NMR
40.3 (CH), 40.6 (CH), 120.7 (CH), 123.9 (CH), 124.5 (CH), 124.9 (CH),
125.1 (CH), 128.4 (CH), 129.3 (CH), 130.6 (CH), 130.8 (C), 135.0 (C),
139.7 (C), 140.6 (C), 142.6 (2ꢅC); HRMS (EI) 332.1528 (C21H20N2O2
requires 332.1525).
4.6.2. (1S,9S)-(þ)-10,10-Dimethyl-5-(20-benzo[h]quinolinyl)-6-
aza-tricyclo[7.1.1.02,7]undeca-2(7),3,5-triene N,N0-dioxide (þ)-(13)
Prepared from bipyridine (þ)-32 (50 mg, 0.14 mmol) and m-
CPBA (49 mg, 0.29 mmol). Purification of the crude product
furnished dioxide (þ)-13 (15 mg, 28%) as a pale yellow solid. Mp
(100 MHz, CDCl3)
d 18.3 (CH3CH), 20.9 (CH3C), 26.3 (CH3-C), 28.7
(CH2-11), 38.9 (CH-8), 41.4 (C-10), 46.8 (CH-9), 47.0 (CH-1), 117.2
(CH-3), 120.7 (CH-300), 122.1 (CH-500), 125.2 (CH-20), 126.8 (CH-60),
127.3 (CH-40), 129.0 (CH-50), 133.3 (CH-4), 136.7 (CH-400), 139.7 (C-
2), 140.4 (C-10), 140.5 (C-30), 149.6 (CH-600), 154.1 (C-200), 157.6 (C-5),
160.6 (C-7); MS (EI) m/z (%) 340 (Mꢆþ, 18), 325 (22, Mꢆþ, –CH3), 82.9
(100); HRMS (EI) 340.1935 (C24H24N2 requires 340.1939).
82–84 ꢁC; [
a]
þ40.9 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz)
D
d
0.69 (s, 3H), 1.28 (d, J¼10.0 Hz, 1H), 1.37 (s, 3H), 2.40–2.44 (m, 1H),
2.63–2.68 (m, 1H), 2.81 (t, J¼5.6 Hz, 1H), 3.08–3.22 (m, 2H), 7.02 (d,
J¼8.0 Hz, 1H), 7.60–7.68 (m, 3H), 7.75 (d, J¼8.8 Hz, 1H), 7.84 (d,
J¼8.0 Hz, 1H), 8.20 (dd, J¼8.0, 5.6 Hz, 2H), 9.02 (d, J¼8.4 Hz, 1H),
9.28 (d, J¼8.0 Hz, 1H); 13C NMR
d 21.2 (CH3), 25.9 (CH3), 31.2 (CH2),
4.5.5. (1S,8R,9S)-(ꢂ)-10,10-Dimethyl-8-isopropyl-5-[30-(pyridin-
200-yl)phenyl]-6-aza-tricyclo[7.1.1.02,7]undeca-2(7),3,5-triene
(ꢂ)-(34d)
31.6 (CH2), 39.4 (CH), 39.5 (C), 46.3 (CH), 123.5 (CH), 123.6 (CH),
124.5 (CH), 125.2 (CH), 125.5 (CH), 126.3 (C), 127.0 (CH), 127.9 (CH),
128.2 (CH), 128.3 (CH), 131.7 (C), 133.7 (C), 135.4 (CH), 145.6 (C),
145.9 (C), 146.0 (C), 146.9 (C), 149.5 (C); HRMS (EI) 382.1679
(C25H22N2O2 requires 382.1681).
Prepared by alkylation of (þ)-34a; purification afforded (ꢂ)-34d
22
(84 mg, 37%). [
a]
ꢂ1.9 (c 1.0, CH2Cl2); IR (NaCl)
n 2957 (m, C-H),
D
1585 (m, C]Car), 1565 (m, C]Car), 1434 (m, C]Car), 777 (s, C–
Har) cmꢂ1; 1H NMR (400 MHz, CDCl3)
0.58 (s, 3H, CH3C-10), 0.81
d
4.6.3. (1S,9S)-(þ)-10,10-Dimethyl-5-(30-phenyl-phenyl)-6-aza-
tricyclo[7.1.1.02,7]undeca-2(7),3,5-triene N,N0-dioxide (þ)-(14a)
Prepared from bipyridine (þ)-33a (50 mg, 0.15 mmol) and m-
CPBA (54 mg, 0.32 mmol). Purification of the crude product gave
(d, J¼7.0 Hz, 3H, CHCH3), 1.18 (d, 0J¼7.0 Hz, 3H, CHCH03), 1.35 (d,
J¼9.8 Hz, 1H, 11-H), 1.36 (s, 3H, CH3 C-10), 2.32 (td, J¼5.9, 1.8 Hz, 1H,
9-H), 2.52 (dt, J¼9.8, 5.8 Hz, 1H, 11-H0), 2.68 (t, J¼5.8 Hz, 1H, 1-H),
2.80–2.90 (m, 1H, CH(CH3)2), 2.93 (dd, J¼4.2, 1.8 Hz, 1H, 8-H), 7.16
(ddd, J¼7.5, 4.1, 1.1 Hz, 1H, 500-H), 7.19 (d, J¼7.8 Hz, 1H, 4-H), 7.48 (d,
J¼7.8 Hz, 1H, 3-H), 7.50 (t, J¼7.7 Hz, 1H, 50-H), 7.69 (td, J¼7.5 ,1.7 Hz,
1H, 400-H), 7.75 (dt, J¼7.5, 1.1 Hz, 1H, 300-H), 7.94 (d, J¼7.8 Hz, 1H, 60-
H), 8.06 (d, J¼7.8 Hz, 1H, 40-H), 8.55 (s, 1H, 20-H), 8.65 (ddd, J¼4.1,
dioxide (þ)-14a as a yellowish amorphous solid (15 mg, 28%). [
a]
D
þ67.8 (c 0.5, CHCl3); 1H NMR (CDCl3, 400 MHz)
d 0.67 (s, 3H), 1.27
(d, J¼9.6 Hz, 1H), 1.38 (s, 3H), 2.40–2.43 (m, 1H), 2.63–2.68 (m, 1H),
2.81 (t, J¼5.6 Hz, 1H), 3.07–3.20 (m, 2H), 7.00 (d, J¼7.6 Hz, 1H),
7.34–7.45 (m, 3H), 7.72 (d J¼8.0 Hz, 1H), 7.85 (t, J¼8.0 Hz, 1H), 8.02
(d, J¼8.4 Hz, 2H), 8.13 (d, J¼8.0 Hz, 1H), 8.85 (d, J¼8.0 Hz, 1H); 13C
1.7, 1.1 Hz, 1H, 600-H); 13C NMR (100 MHz, CDCl3)
d 20.1 (CH3CH),
21.0 (CH3), 22.3 (C0H3CH), 26.3 (CH3), 29.4 (CH2-11), 30.2
(CH(CH3)2), 41.2 (CH-9), 41.8 (C-10), 46.5 (CH-1), 49.1 (CH-8), 117.0
(CH-3), 120.6 (CH-300), 122.0 (CH-500), 125.0 (CH-20), 126.7 (CH-60),
127.2 (CH-40), 129.0 (CH-50), 133.3 (CH-4), 136.7 (CH-400), 139.6 (C-
2), 140.5 (C-10), 140.9 (C-30), 149.5 (CH-600), 153.6 (C-200), 157.5 (C-5),
159.1 (C-7); MS (EI) m/z (%) 368 (Mꢆþ, 22), 325 (Mꢆþꢂi-Pr, 100), 283
(71); HRMS (EI) 368.2249 (C26H28N2 requires 368.2252).
NMR d 15.9 (CH3), 20.5 (CH3), 25.5 (CH2), 26.0 (CH2), 33.9 (CH), 34.2
(C), 41.0 (CH), 117.5 (CH), 119.4 (CH), 119.6 (CH), 121.9 (CH), 122.3
(CH), 122.8 (2ꢅCH), 124.2 (CH), 124.4 (2ꢅCH), 127.3 (C), 127.4 (C),
135.5 (C), 138.8 (C), 141.1 (C), 144.6 (C); HRMS (EI) 358.1682
(C23H22N2O2 requires 358.1681).
4.6.4. (1S,8R,9S)-(þ)-8,10,10-Trimethyl-5-(30-phenyl-phenyl)-6-
aza-tricyclo[7.1.1.02,7]undeca-2(7),3,5-triene N,N0-dioxide (þ)-(14b)
Prepared from bipyridine (þ)-33b (40 mg, 0.12 mmol) and m-
CPBA (45 mg, 0.26 mmol). Purification of the crude product affor-
4.6. General procedure for the preparation of bipyridine
N,N0-dioxides 12–158
ded dioxide (þ)-14b (20 mg, 44%) as an amorphous solid. [
a]
D
m-Chloroperoxybenzoic acid (70%, 106 mg, 0.60 mmol,
4.0 equiv) was added portion-wise to a respective cool (0 ꢁC)
þ16.6 (c 0.5, CHCl3); 1H NMR (CDCl3, 400 MHz)
d 0.61 (s, 3H), 1.36
(s, 3H), 1.41 (d, J¼10.0 Hz, 1H), 1.44 (d, J¼6.8 Hz, 3H), 2.08–2.11 (m,

11344
A.V. Malkov et al. / Tetrahedron 64 (2008) 11335–11348
1H), 2.48–2.53 (m, J¼6.0 Hz, 1H), 2.76 (t, J¼5.6 Hz, 1H), 3.34–3.38
(m, 1H), 6.88 (d, J¼7.6 Hz, 1H), 7.27–7.47 (m, 6H), 7.54 (d, J¼7.6 Hz,
4.6.8. (1S,8R,9S)-(ꢂ)-8,10,10-Trimethyl-8-isopropyl-5-[30-(pyridin-
200-yl)phenyl]-6-aza-tricyclo[7.1.1.02,7]undeca-2(7),3,5-triene
N,N0-dioxide (ꢂ)-(15b)
1H), 7.77 (d, J¼6.0 Hz, 2H); 13C NMR
d 15.2 (CH3), 18.6 (CH3), 20.1
(CH3), 24.9 (CH2), 37.2 (CH), 39.6 (C), 45.7 (CH), 46.1 (CH), 121.5
(CH), 123.6 (CH), 124.1 (CH), 126.3 (CH), 126.5 (CH), 127.0 (2ꢅCH),
128.4 (CH), 128.6 (2ꢅCH), 131.8 (C), 140.2 (C), 143.0 (C), 145.8 (C),
148.8 (C), 173.1 (C); HRMS (EI) 372.1838 (C24H24N2O2 requires
372.1838).
Prepared from (þ)-34b; purification afforded (ꢂ)-15b (23 mg,
14
42%). [
a]
ꢂ31.0 (c 1.0, CHCl3); IR (NaCl)
n 2933 (m, C–H), 1585 (m,
D
C]Car), 1462 (m, C]Car), 1431 (m, C]Car), 1216 (m, Nþ–Oꢂ), 761
(s, C–Har) cmꢂ1; 1H NMR (400 MHz, CDCl3)
d
0.57 (s, 3H, CH3C),1.33
0
(s, 3H, CH3 C), 1.36 (d, J¼9.9 Hz, 1H, 11-H), 1.41 (d, J¼6.6 Hz, 3H,
CH3CH), 2.08 (td, J¼6.0, 2.8 Hz, 1H, 9-H), 2.48 (dt, J¼9.9, 6.0 Hz, 1H,
11-H0), 2.71 (t, J¼6.0 Hz, 1H, 1-H), 3.33 (qd, J¼6.6, 2.8 Hz, 1H, 8-H),
6.82 (d, J¼7.8 Hz, 1H, 4-H), 7.12–7.18 (m, 2H, 3-H, 500-H), 7.22 (td,
J¼7.7, 1.1 Hz, 1H, 400-H), 7.42 (dd, J¼7.7, 2.0 Hz, 1H, 300-H), 7.48
(t, J¼7.8 Hz, 1H, 50-H), 7.77 (dd, J¼7.8, 1.7 Hz, 2H, 60-H, 40-H), 8.13 (t,
J¼1.7 Hz, 1H, 20-H), 8.24 (dd, J¼6.4, 1.1 Hz, 1H, 600-H); 13C NMR
4.6.5. (1S,8R,9S)-(ꢂ)-8-Butyl-10,10-dimethyl-5-(30-phenyl-
phenyl)-6-aza-tricyclo[7.1.1.02,7]undeca-2(7),3,5-triene
N,N0-dioxide (ꢂ)-(14c)
Prepared from bipyridine (þ)-33c (50 mg, 0.13 mmol) and
m-CPBA (50 mg, 0.29 mmol). Purification of the crude product
furnished dioxide (ꢂ)-14c (25 mg, 47%) as an amorphous solid.
(100 MHz, CDCl3) d 14.7 (CH3CH), 20.5 (CH3), 25.8 (CH3), 28.2 (CH2-
[
a
]
ꢂ27.1 (c 0.5, CHCl3); 1H NMR (CDCl3, 400 MHz)
d
0.58 (s, 3H),
11), 35.0 (CH-8), 41.5 (C-10), 46.8 (CH-1), 47.3 (CH-9), 123.1 (CH-3),
124.3 (CH-4), 124.6 (CH-500), 125.9 (CH-400), 127.7 (CH-300), 128.0
(CH-50), 129.7 (CH-60), 130.6 (CH-40), 130.8 (CH-20), 132.3 (C-2),
133.5 (C-10), 140.3 (CH-600), 144.6 (C-30), 147.0 (C-200), 149.0 (C-5),
150.1 (C-7); MS (FAB) m/z (%) 373 ((MþH)þ, 31), 338 (100), 215 (10),
75 (96); HRMS (FAB) 373.1919 (C24H25N2O2 (MþH)þ requires
373.1916).
D
0.83 (t, J¼7.2 Hz, 3H), 1.30 (d, J¼10.0 Hz, 1H), 1.37–1.42 (m, 8H),
2.28–2.32 (m, 1H), 2.46–2.52 (m, 1H), 2.51–2.57 (m, 1H), 2.76 (t,
J¼5.6 Hz, 1H), 3.12–3.14 (m, 1H), 6.86 (d, J¼8.0 Hz, 1H), 7.31 (dd,
J¼8.0, 2.0 Hz, 2H), 7.34–7.40 (m, 3H), 7.44 (dd, J¼8.0, 2.0 Hz, 1H),
7.53 (dd, J¼8.0, 2.0 Hz, 1H), 7.77 (dd, J¼8.0, 2.0 Hz, 2H); 13C NMR
d
13.3 (CH3), 19.8 (CH3), 21.8 (CH2), 25.0 (CH3), 26.5 (CH2), 27.3
(CH2), 29.4 (CH2), 39.4 (CH), 40.2 (C), 42.7 (CH), 45.9 (CH), 121.4
(CH), 123.6 (CH), 124.1 (CH), 126.3 (CH), 126.5 (CH), 127.0 (2ꢅCH),
128.4 (CH), 128.6 (2ꢅCH), 131.7 (C), 140.2 (C), 142.9 (C), 145.3 (C),
148.9 (C), 172.8 (C); HRMS (EI) 414.2306 (C27H30N2O2 requires
414.2307).
4.6.9. (1S,8R,9S)-(ꢂ)-10,10-Dimethyl-8-isopropyl-5-[30-(pyridin-
200-yl)phenyl]-6-aza-tricyclo[7.1.1.02,7]undeca-2(7),3,5-triene
N,N0-dioxide (ꢂ)-(15d)
Prepared from (ꢂ)-34d; purification afforded (ꢂ)-15d (27 mg,
14
45%). [
a
]
D
ꢂ64.0 (c 1.0, CHCl3); IR (NaCl)
n 2935 (m, C–H), 1587 (m,
4.6.6. (1S,8R,9S)-(þ)-10,10-Dimethyl-8-isopropyl-5-(30-phenyl-
phenyl)-6-aza-tricyclo[7.1.1.02,7]undeca-2(7),3,5-triene N,N0-
dioxide (þ)-(14d)
C]Car), 1465 (m, C]Car), 1436 (m, C]Car), 1216 (m, Nþ–Oꢂ), 762
(s, C–Har) cmꢂ1 1H NMR (400 MHz, CDCl3)
0.53 (s, 3H, CH3C),
;
d
0.88 (d, J¼7.0 Hz, 3H, CHCH3), 0.95 (d, J¼7.0 Hz, 3H, CHCH03), 1.33 (s,
3H, CH3C), 1.54 (d, J¼9.9 Hz, 1H, 11-H), 2.31 (td, J¼5.8, 2.4 Hz, 1H, 9-
H), 2.46 (dt, J¼9.9, 5.8 Hz, 1H, 11-H0), 2.67 (t, J¼5.8 Hz, 1H, 1-H),
3.10–3.20 (m, 2H, 8-H, CH(CH3)2), 6.81 (d, J¼7.8 Hz, 1H, 3-H), 7.11–
7.17 (m, 2H, 3-H, 500-H), 7.21 (td, J¼7.7, 1.2 Hz, 1H, 400-H), 7.42 (dd,
J¼0 7.7, 2.0 Hz,1H, 300-H), 7.48 (t, J¼7.8 Hz,1H, 50-H), 7.74–7.78 (m, 2H,
6 -H, 40-H), 8.09 (t, J¼1.5 Hz, 1H, 20-H), 8.24 (dd, J¼6.4, 1.2 Hz, 1H,
Prepared from bipyridine (ꢂ)-33d (20 mg, 0.05 mmol) and
m-CPBA (21 mg, 0.11 mmol). Purification of the crude product gave
dioxide (þ)-14d (9 mg, 45%) as an amorphous solid. [
a
]
þ7.6 (c
D
0.5, CHCl3); 1H NMR (CDCl3, 400 MHz)
d
0.56 (s, 3H), 0.91 (d,
J¼7.2 Hz, 3H), 0.97 (d, J¼7.2 Hz, 3H), 1.35 (s, 3H), 1.58 (d, J¼10.0 Hz,
1H), 2.26–2.34 (m, 1H), 2.41–2.52 (m, 1H), 2.76 (t, J¼5.2 Hz, 1H),
3.12–3.19 (m, 1H), 3.17–3.22 (m, 1H), 6.88 (d, J¼8.0 Hz, 1H), 7.19–
7.31 (m, 3H), 7.33–7.38 (m, 3H), 7.44 (d, J¼8.0 Hz, 1H), 7.77 (d,
600-H); 13C NMR (100 MHz, CDCl3)
d 20.6 (CH3C), 20.9 (CH3CH), 21.5
(C0H3CH), 25.8 (C0H3C), 27.8 (CH(CH3)2), 28.2 (CH2-11), 42.3 (CH-9),
42.9 (C-10), 45.5 (CH-8), 46.6 (CH-1), 123.0 (CH-3), 124.3 (CH-4),
124.6 0(CH-500), 125.8 (CH-400), 127.7 (CH-300), 128.1 (CH-50), 129.6
(CH-6 ), 130.5 (CH-40), 130.8 (CH-20), 132.4 (C-2), 133.8 (C-10), 140.3
(CH-600), 145.2 (C-30), 147.2 (C-200), 149.0 (C-5), 149.2 (C-7); MS (FAB)
m/z (%) 401 ((MþH)þ, 100), 385 ((MþH)þꢂO, 26), 338 (23), 71 (20);
HRMS (FAB) 401.2232 (C26H29N2O2 (MþH)þ requires 401.2229).
J¼8.0 Hz, 2H); 13C NMR
d 14.0 (CH3), 19.6 (CH3), 22.1 (CH3), 24.9
(CH3), 25.7 (CH2), 29.4 (CH), 31.4 (CH), 40.3 (C), 42.1 (CH), 45.3
(CH), 121.4 (CH), 123.6 (CH), 124.0 (CH), 126.3 (CH), 126.4 (CH),
127.0 (2ꢅCH), 128.5 (CH), 128.6 (2ꢅCH), 131.8 (C), 140.7 (C), 142.7
(C), 145.3 (C), 148.9 (C), 171.7 (C); HRMS (EI) 400.2152 (C26H28N2O2
requires 400.2151).
4.6.7. (1S,9S)-(ꢂ)-10,10-Dimethyl-5-[30-(pyridin-20-yl)phenyl]-6-
aza-tricyclo[7.1.1.02,7]undeca-2(7),3,5-triene N,N-dioxide (ꢂ)-(15a)
4.7. General method for the preparation of isoquinoline
N-oxides (R)-16a–d8
Prepared from (þ)-34a; purification afforded (ꢂ)-15a (32 mg,
21
60%). [
a]
ꢂ22.3 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3)
d
0.72
The oxidation was carried out on a 0.22–0.28 mmol scale. A
solution of m-CPBA (1.5 equiv) in CH2Cl2 (5 mL) was added to
a cooled stirred solution of the respective isoquinoline derivative
(R)-42a–d (1.0 equiv) in CH2Cl2 (2 mL) at 0 ꢁC and the resulting
mixture was stirred at room temperature for 2 d. After this period
the mixture was treated with aqueous saturated Na2CO3 (10 mL)
and then extracted with CH2Cl2 (3ꢅ10 mL). The combined organic
extracts were dried over MgSO4 and the solvent was removed in
vacuo to give the crude product, which was purified by column
chromatography on silica gel (2 g) using a mixture of petroleum
ether and ethyl acetate (5:1) to elute the unreacted starting ma-
terial, followed by ethyl acetate, to give the pure product.
D
0
(s, 3H, CH3C), 1.31 (d, J¼9.8 Hz, 1H, 11-H), 1.42 (s, 3H, CH3 C), 2.44
(tt, J¼5.9, 2.9 Hz, 1H, 9-H), 2.69 (dt, J¼9.8, 5.9 Hz, 1H, 9-H0), 2.81 (t,
J¼5.9 Hz, 1H, 1-H), 3.10 (dd, J¼19.2, 5.9 Hz, 1H, 8-H), 3.18
(dd, J¼19.2, 5.9 Hz, 1H, 7-H0), 6.93 (d, J¼7.8 Hz, 1H, 3-H), 7.22 (ddd,
J¼7.6, 6.5, 2.0 Hz, 1H, 500-H), 7.27 (d, J¼7.8 Hz, 1H, 4-H), 7.30 (td,
J¼7.6, 1.3 Hz, 1H, 400-H), 7.52 (dd, J¼7.6, 2.0 Hz, 1H, 300-H), 7.56
(t, J¼7.9 Hz, 1H, 50-H), 7.87 (ddd, J¼7.9, 1.7, 1.2 Hz, 1H, 60-H), 7.90
(ddd, J¼7.9, 1.7, 1.2 Hz, 1H, 40-H), 8.25 (t, J¼1.7 Hz, 1H, 20-H), 8.31
(dd, J¼6.5, 1.3 Hz, 1H, 600-H); 13C NMR (100 MHz, CDCl3)
d 21.1
(CH3), 25.8 (CH3), 31.1 (CH2-8), 31.5 (CH2-11), 39.3 (CH-9, C-10),
46.1 (CH-1), 123.1 (CH-3), 124.0 (CH-4), 124.6 (CH-500), 125.8 (CH-
400), 127.7 (CH-300), 128.0 (CH-50), 129.8 (CH-40), 130.5 (CH-60), 130.7
(CH-20), 132.3 (C-2), 133.3 (C-10), 140.3 (CH-600), 144.6 (C-30),
146.4 (C-200), 146.8 (C-5), 149.0 (C-7); MS (FAB) m/z (%) 359
((MþH)þ, 100); HRMS (FAB) 359.1829 (C23H23N2O2 (MþH)þ re-
quires 359.1827).
4.7.1. (R)-(þ)-1–(2-Methoxy-naphthalen-1-yl)-3-methyl-5,6,7,8-
tetrahyroisoquinoline 2-oxide (R)-(þ)-(16a)
Prepared from (R)-(þ)-42a30a (90 mg, 0.30 mmol) and m-CPBA
(86 mg, 0.50 mmol). Purification of the crude product gave N-oxide

A.V. Malkov et al. / Tetrahedron 64 (2008) 11335–11348
11345
(R)-(þ)-16a as a pale yellow solid (38 mg, 40%). Mp 138–140 ꢁC;
with CH2Cl2 (2ꢅ30 mL). The combined organic layers were washed
with 10% aqueous Na2CO3 (2ꢅ10 mL), dried over MgSO4 and
evaporated. The residue was chromatographed on a column of on
silica gel (12 g) with a mixture of petroleum ether and ethyl acetate
(1:1) to afford the corresponding monooxide (100 mg, 20%), fol-
lowed by dioxide 17b (531 mg, 57%), both as white solids that
decomposed on heating before melting. Monooxide: amorphous
[
a]
þ206.0 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz)
d 1.58–1.72
D
(m, 2H), 1.82 (quin, J¼6.8 Hz, 2H), 2.05–2.12 (m, 1H), 2.24–2.31 (m,
1H), 2.59 (s, 3H), 2.84 (t, J¼6.4 Hz, 2H), 3.91 (s, 3H), 7.12–7.15 (m,
2H), 7.33–7.45 (m, 3H), 7.84–7.86 (m, 1H), 7.99 (d, J¼9.2 Hz, 1H); 13C
NMR d 17.9 (CH3), 22.1 (CH2), 22.2 (CH2), 25.8 (CH2), 28.6 (CH2), 56.5
(CH3), 113.2 (CH), 115.8 (C), 123.2 (CH), 123.7 (CH), 125.6 (CH), 127.4
(CH), 128.3 (CH), 129.1 (C), 130.7 (CH), 132.0 (C), 133.8 (C), 135.7 (C),
145.8 (C), 145.8 (C), 154.3 (C); HRMS (EI) 319.1574 (C21H21NO2 re-
quires 319.1572).
solid. 1H NMR (CDCl3, 400 MHz)
d
7.20–8.10 (m); 13C NMR (CDCl3,
400 MHz) 117.9 (CH), 124.8 (CH), 125.1 (CH), 126.1 (CH), 126.2 (C),
d
126.8 (C), 126.9 (CH), 127.2 (CH), 127.3 (CH), 127.6 (CH), 128.1 (2CH),
128.4 (CH), 128.5 (CH), 128.66 (CH), 128.75 (CH), 128.83 (CH), 129.0
(CH), 129.37 (CH), 129.40 (CH), 129.44 (C), 130.0 (CH), 130.7 (CH),
132.9 (C), 137.3 (C), 139.5 (C), 144.2 (C), 147.2 (C), 151.4 (C), 152.5 (C);
4.7.2. (R)-(þ)-1-(2-Methoxy-naphthalen-1-yl)-3-phenyl-5,6,7,8-
tetrahydroisoquinoline 2-oxide (R)-(þ)-(16b)
Prepared from (R)-(þ)-42b30a (100 mg, 0.28 mmol) and m-CPBA
(74 mg, 0.42 mmol). Purification of the crude product gave N-oxide
IR (KBr) n ;
3054, 1620, 1496, 1314, 1233, 885, 770, 746, 700 cmꢂ1
FABMS m/z (%) 425 ([MþH]þ, 50), 359 (12), 331 (20), 282 (100), 280
(R)-(þ)-16b as a pale yellow solid (37 mg, 35%). Mp 95–97 ꢁC; [
a]
D
(18), 256 (12), 240 (4), 150 (2), 99 (30), 71 (60), 57 (78). Dioxide 17b:
þ220.0 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz)
d
1.56–1.68 (m,
1H NMR (CDCl3, 400 MHz)
d
7.20 (d, J¼8.6 Hz, 2H), 7.41–7.49 (m,
8H), 7.54–7.58 (m, 2H), 7.89–7.93 (m, 6H), 7.81 (s, 2H); 13C NMR
(CDCl3, 400 MHz) 123.4 (CH), 125.4 (CH), 127.2 (CH), 127.9 (CH),
128.5 (CH), 128.7 (C), 128.9 (C), 129.3 (CH), 129.6 (CH), 130.0 (CH),
132.5 (C), 138.8 (C),147.4 (C); IR (KBr) 3424, 3054,1595,1487,1357,
1312, 1213, 1129, 949, 896, 771, 689 cmꢂ1; EIMS m/z (%) 440 (Mꢆþ
2H), 1.77 (quin, J¼5.1 Hz, 2H), 2.02–2.09 (m, 1H), 2.21–2.29 (m, 1H),
2.81 (t, J¼6.2 Hz, 2H), 3.83 (s, 3H), 7.16–7.21 (m, 2H), 7.24–7.35 (m,
6H), 7.67 (d, J¼7.4 Hz, 1H), 7.83 (d, J¼8.4 Hz, 2H), 7.89 (d, J¼9.1 Hz,
d
1H); 13C NMR
d
21.0 (CH2), 21.1 (CH2), 25.0 (CH2), 28.7 (CH2), 55.7
n
(CH3), 113.3 (CH), 114.6 (C), 123.8 (CH), 126.5 (CH), 127.1 (2ꢅCH),
127.5 (CH), 127.9 (CH), 128.1 (C), 128.3 (C), 128.3 (2ꢅCH), 128.9 (CH),
129.7 (CH), 130.8 (CH), 132.2 (C), 132.4 (C), 134.3 (C), 135.5 (C), 145.4
(C), 153.3 (C); HRMS (EI) 381.1727 (C26H23NO2 requires 381.1729).
,
9), 424 (13), 407 (100), 239 (66), 204 (64), 105 (29), 77 (32); HRMS
(EI) 440.1520 (C30H20N2O2 requires 440.1525). The resolution
of racemic dioxide 17b was carried out by HPLC in batches of 1.5 mg
each on Chiralpak OP(þ), (250ꢅ46 mm) MeOH, 0.5 mL/min, which
4.7.3. (R)-(þ)-1-(2-Methoxy-naphthalen-1-yl)-3-(3,4,5-
trimethoxyphenyl)-5,6,7,8-tetrahydroisoquinoline
2-oxide (R)-(þ)-(16c)
afforded (þ)-17b as the faster eluting enantiomer: [
a
]
þ178 (c
D
0.32, CHCl3). The slower component was (ꢂ)-17b, [ D ꢂ184 (c 0.45,
a
]
CHCl3). Each enantiomer was obtained in >99% ee (t(þ)¼24.55 min,
Prepared from (R)-(þ)-42c30b (100 mg, 0.2 mmol) and m-CPBA
(57 mg, 0.3 mmol). Purification of the crude product gave N-oxide
t(ꢂ)¼57.00 min).
(R)-(þ)-16c as a white solid (59 mg, 57%). Mp 88–90 ꢁC; [
a
]
D þ38.0
4.7.6. Benzo[h]quinoline-2-carboxylic acid (36)26
(c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz)
d
1.53–1.65 (m, 2H), 1.77
A mixture of 10 M HCl (75 mL) and benzo[h]quinoline-2-car-
bonitrile 3526 (5.00 g, 24.5 mmol) was refluxed for two days. The
reaction mixture was then cooled to room temperature and water
(60 mL) was added. The aqueous phase was extracted with CH2Cl2
(3ꢅ50 mL) and the organic layer was washed with aqueous satu-
rated aqueous NaHCO3 (50 mL). The organic extracts were dried
over MgSO4 and the solvent was removed in vacuo to afford pure
acid 36 (5.895 g, 99%) as a yellow crystalline solid. Mp 180–181 ꢁC;
(quin, J¼6.2 Hz, 2H), 1.98–2.07 (m, 1H), 2.19–2.27 (m, 1H), 2.81 (t,
J¼6.3 Hz, 2H), 3.78 (s, 3H), 3.80 (s, 6H), 3.83 (s, 3H), 7.07 (s, 2H),
7.16–7.20 (m, 2H), 7.24–7.32 (m, 3H), 7.77 (d, J¼8.8 Hz, 1H), 7.89 (d,
J¼9.0 Hz, 1H); 13C NMR
d 22.03 (CH2), 22.17 (CH2), 26.00 (CH2),
28.79 (CH2), 56.41 (2ꢅCH3), 56.50 (CH3), 60.85 (CH3), 107.62
(2ꢅCH), 113.30 (CH), 115.97 (C), 123.31 (CH), 123.82 (CH), 126.46
(CH), 127.44 (CH), 128.35 (CH), 129.18 (C), 129.55 (C), 130.92 (CH),
131.92 (C), 135.29 (C), 136.49 (C), 138.81 (C), 146.37 (C), 152.80
(2ꢅC), 154.34 (C); HRMS (EI) 471.2047 (C29H29NO5 requires
471.2046).
1H NMR (CDCl3, 400 MHz)
d 7.69–7.75 (m, 3H), 7.88–7.91 (m, 2H),
8.34 (t, J¼8.4 Hz, 2H), 9.11 (d, J¼9.2 Hz, 1H), 12.80 (s, 1H); 13C NMR
d
120.5 (CH), 124.0 (CH), 124.7 (CH), 128.0 (CH), 128.4 (CH), 129.2
(C), 129.4 (CH), 130.2 (C), 130.8 (CH), 134.0 (C), 138.5 (CH), 144.1 (C),
4.7.4. (R)-(þ)-3-Fur-2-yl-1-(2-methoxy-naphthalen-1-yl)-5,6,7,8-
tetrahydroisoquinoline 2-oxide (R)-(þ)-(16d)
144.5 (C), 164.4 (C); IR (KBr)
223.0632 (C14H9NO2 requires 223.0633).
n
2580–3050, 1685 cmꢂ1; HRMS (EI)
Prepared from (R)-(þ)-42d30b (100 mg, 0.28 mmol) and m-CPBA
(74 mg, 0.42 mmol). Purification of the crude product gave N-oxide
(R)-(þ)-16d as a pale yellow solid (21 mg, 20%). Mp 144–146 ꢁC;
4.7.7. Methyl benzo[h]quinoline-2-carboxylate (37)
Concd. H2SO4 (7.910 g, 80.7 mmol) was added slowly to a solu-
tion of benzo[h]quinoline-2-carboxylic acid 36 (6.000 g, 26.9 mmol)
in methanol (100 mL) and the reaction mixture was then stirred
under reflux for 6 h. The reaction mixture was cooled to room
temperature, the methanol was removed by evaporation and the
residue was poured onto ice. Aqueous concd. NH3 (20 mL) was
added slowly and the product was extracted with CH2Cl2
(3ꢅ25 mL). The combined organic extracts were dried over MgSO4
and the solvent was removed in vacuo to furnish the crude product,
which was recrystallized from hexane to give the pure ester 37
(5.650 g, 88%) as an orange solid. Mp 64–66 ꢁC; 1H NMR (CDCl3,
[
a
]
D þ175.3 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz)
d 1.50–1.66 (br
m, 2H), 1.76 (quin, J¼6.0 Hz, 2H), 1.97–2.04 (m, 1H), 2.16–2.24 (m,
1H), 2.78–2.87 (m, 2H), 3.80 (s, 3H), 6.46 (dd, J¼3.6, 2.0 Hz, 1H), 7.10
(d, J¼9.2 Hz, 1H), 7.23–7.35 (m, 4H), 7.48 (s, 1H), 7.76 (d, J¼9.1 Hz,
1H), 7.91 (t, J¼8.8 Hz, 2H); 13C NMR
d 22.1 (CH2), 22.2 (CH2), 25.9
(CH2), 28.9 (CH2), 56.5 (CH3), 112.4 (CH), 113.3 (CH), 115.5 (C), 115.8
(CH), 121.4 (CH), 123.1 (CH), 123.9 (CH), 127.6 (CH), 128.3 (C), 128.4
(CH), 129.2 (C), 130.9 (CH), 132.0 (C), 133.7 (C), 137.8 (C), 142.9 (CH),
145.9 (C), 154.4 (C); HRMS (EI) 371.1521 (C24H21NO3 requires
371.1521).
400 MHz)
d
4.01, (s, 3H), 7.62 (d, J¼8.8 Hz, 1H), 7.63–7.72 (m, 2H),
4.7.5. 3,30-Diphenyl-[1,10]-biisoquinolinyl-N,N0-dioxide (17b)
7.79–7.83 (m, 2H), 8.23 (q, J¼8.4 Hz, 2H), 9.34 (d, J¼8.0 Hz, 1H); 13C
m-CPBA (2.6 g, 12 mmol, 10 equiv) was added to a pre-cooled
(0 ꢁC) solution of biisoquinoline 46 (500 mg, 1.2 mmol, 1.0 equiv) in
CH2Cl2 (22 mL), the reaction mixture was allowed to reach room
temperature and then stirred for 48 h. The resulting mixture was
diluted with water (30 mL) and the aqueous layer was extracted
NMR d 53.0 (CH3), 122.2 (CH), 124.7 (CH), 125.0 (CH), 127.6 (CH),
127.9 (CH), 128.2 (C), 128.8 (CH), 130.2 (CH), 131.5 (C), 133.7 (C),
136.7 (CH), 146.2 (C), 146.3 (C), 166.3 (C); IR (KBr)
HRMS (EI) 237.0791 (C15H11NO2 requires 237.0790). For the
method, see Ref. 25.
n
1733 (s) cmꢂ1
;

11346
A.V. Malkov et al. / Tetrahedron 64 (2008) 11335–11348
4.7.8. (R)-(þ)-1-(2-Methoxy-1-naphthyl)-3-methyl-5,6,7,8-
4.7.13. 1-Chloro-3-phenylisoquinoline (45)
tetrahydroisoquinoline (R)-(þ)-(42a)30a
25
Mp 160–161 ꢁC (pentane); [
a
]
þ138.9 (c 0.1, toluene); 1H NMR
4.7.13.1. Method A. A mixture of POCl3 (5 mL, 54 mmol) and PCl5
(100 mg, 0.48 mmol) was added to 3-phenyl-2H-isoquinoline 44
(564 mg, 2.3 mmol) and the mixture was stirred at 120 ꢁC for 2 h.
The mixture was then cooled and poured onto ice, the precipitate
was collected and washed successively with 40% aqueous ammonia
and water. The precipitate was dissolved in ethyl acetate (50 mL)
and the solution was washed with water dried over MgSO4, and
evaporated. The residue was crystallized from hexane to afford 45
(350 mg, 63%). Mp 68–69 ꢁC (ethyl acetate/hexane); 1H NMR
D
(CDCl3, 400 MHz)
d
7.80 (d, 1H, J¼9.1 Hz), 7.73–7.71 (m, 1H), 7.28–
7.21 (m, 3H), 7.05–7.03 (m, 1H), 6.87 (s, 1H), 3.78 (s, 3H), 2.76–2.73
(m, 2H), 2.47 (s, 3H), 2.33–2.26 (m, 1H), 2.07–2.0 (m, 1H), 1.71–1.5
(m, 4H); 13C NMR (CDCl3)
d 22.8, 23.4, 24.5, 25.7, 29.8, 57.0, 114.0,
123.1, 123.9, 124.0, 125.0, 126.9, 128.3, 129.7, 130.0, 130.4, 133.6,
147.0, 154.2, 154.8, 155.5; MS (70 eV), m/z 303 (74) [Mþ], 302 (100),
284 (57), 272 (38), 259 (24). Enantiomeric purity by HPLC analysis
was >99% ee; HPLC conditions: Chiralcel OD-H, hexane/ethanol
99.95:0.05, 1.5 mL/min, t1¼4.72 min, t2¼5.94 min.
(CDCl3, 400 MHz)
d
7.35 (tt, J¼7.4, 1.3 Hz, 1H), 7.40–7.46 (m, 2H),
7.58 (ddd, J¼8.3, 6.9, 1.2 Hz, 1H), 7.67 (ddd, J¼8.1, 6.9, 1.2 Hz, 1H),
7.82 (d, J¼8.2 Hz, 1H), 7.94 (s, 1H), 8.03–8.07 (m, 2H), 8.26 (d,
4.7.9. (R)-(þ)-1-(2-Methoxy-1-naphthyl)-3-phenyl-5,6,7,8-
tetrahydroisoquinoline (R)-(þ)-(42b)30a
J¼8.0 Hz, 1H); 13C NMR (CDCl3, 400 MHz)
d 116.3 (CH), 126.0 (C),
25
Mp 200–201 ꢁC (ethyl acetate); [
a
]
þ202.5 (c 0.1, toluene); 1H
126.5 (CH), 126.9 (CH), 127.4 (CH), 128.3 (2ꢅCH), 128.9 (2ꢅCH),
D
NMR (CDCl3, 400 MHz)
8.12–8.08 (m, 1H), 7.78 (s, 1H), 7.69–7.55 (m, 7H), 4.11 (s, 3H), 3.18
d
8.28–8.26 (m, 2H), 8.17 (d, 1H, J¼9.1 Hz),
129.0 (CH), 131.3 (CH), 138.0 (C), 138.7 (C), 150.3 (C), 151.4 (C); IR
(KBr) n
1950, 1562, 1312, 1258, 979, 850, 764, 688 cmꢂ1; EIMS m/z
(m, 2H), 2.81–2.73 (m,1H), 2.51–2.44 (m,1H), 2.11–1.86 (m, 4H); 13C
(%) 239 (Mꢆþ, 100), 204 (54), 176 (13), 151 (5), 119 (5), 102 (9), 88 (9),
35
NMR (CDCl3)
d
156.3, 154.6, 154.4, 147.4, 140.6, 133.8, 132.5, 130.2,
75 (6); HRMS (EI) 239.0506 (C15H ClN requires 239.0502).
10
129.8, 129.0 (2ꢅ), 128.7, 128.4, 127.6 (2), 127.0, 125.2, 124.3, 124.0,
120.7, 114.3, 57.2, 30.2, 26.0, 23.5, 22.9; MS (70 eV), m/z 365 (72)
[Mþ], 364 (100), 346 (40), 334 (27), 321 (18), 306 (6). Enantiomeric
purity by HPLC analysis >99% ee; HPLC conditions: Chiralpak AD-H,
hexane/ethanol 99:1, 1.0 mL/min, t1¼6.67 min, t2¼8.31 min.
4.7.13.2. Method B. Phosphoryl chloride (2.56 g, 16.70 mmol,
3.3 equiv) was added to a solution of 51 (1.2 g, 5.06 mmol,1.0 equiv)
in chloroform (20 mL) and the mixture was refluxed for 3 h, then
cooled to room temperature and poured onto ice. Concentrated
aqueous ammonia was added dropwise until the solution was basic.
The layers were separated and the aqueous phase was extracted
with CH2Cl2 (2ꢅ20 mL). Combined organic extracts were dried over
MgSO4 and concentrated under reduced pressure. The crude resi-
due was purified by flash chromatography on a column of silica gel
(40 g) with a mixture of petroleum ether and ethyl acetate (10:1) to
furnish 45 (0.61 g, 50%) as a white solid: mp 68–69 ꢁC (ethyl ace-
tate/hexane), identical with the product prepared by Method A.
4.7.10. (R)-(þ)-1-(2-Methoxy-1-naphthyl)-3-(3,4,5-trimethoxy-
phenyl)-5,6,7,8-tetrahydroisoquinoline (R)-(þ)-(42c)30b
25
Mp 140–141 ꢁC (benzene/hexane); [
a
]
D
þ173.2 (c 0.3, CHCl3);
1H NMR (CDCl3, 400 MHz)
d
7.83 (d, J¼8.9 Hz, 1H), 7.77–7.72 (m,
1H), 7.34 (s, 1H), 7.29–7.16 (m, 4H), 7.10 (s, 2H), 3.80 (s, 6H), 3.78 (s,
3H), 3.77 (s, 3H), 2.89–2.78 (m, 2H), 2.43–2.35 (m, 1H), 2.14–2.06
(m, 1H), 1.77–1.69 (m, 2H), 1.67–1.61 (m, 1H), 1.6–1.51 (m, 1H); 13C
NMR (CDCl3)
d 156.1, 154.3, 153.7, 147.3, 138.8, 136.5, 133.7, 132.4,
130.0, 129.6, 128.8, 128.3, 126.8, 125.2, 124.2, 123.9, 120.5, 114.2,
104.8, 61.3, 57.1, 56.6, 30.1, 25.9, 23.4, 22.8; MS (70 eV), m/z 455
(100) [Mþ], 440 (20), 436 (25), 424 (19), 227 (12). Enantiomeric
purity by HPLC analysis 91% ee; HPLC conditions: Chiralpak AD-
126, hexane/ethanol 95:5, 1.0 mL/min, t1¼13.8 min, t2¼19.8 min.
4.7.14. 3,30-Diphenyl-[1,10]-biisoquinolinyl (46)
Activated zinc powder (570 mg, 8.7 mmol) was added to a stir-
red blue solution of NiCl2$6H2O (2.07 g, 8.7 mmol) and Ph3P (9.10 g,
34.8 mmol) in DMF (45 mL) at 50 ꢁC and the mixture was stirred at
that temperature for 1 h under argon, during which time the color
of the mixture had changed to red-brown. A solution of 1-chloro-3-
phenylisoquinoline 45 (2.10 g, 8.7 mmol) in DMF (15 mL) was then
added and the mixture was stirred at the same temperature for
another 3 h. The mixture was then cooled to room temperature,
diluted with 40% aqueous ammonia, and the product was extracted
into CH2Cl2 (3ꢅ50 mL), the combined organic extracts were
washed with water (3ꢅ50 mL), dried over MgSO4, and evaporated.
The residue was chromatographed on a column of silica gel (10 g)
with a mixture of petroleum ether and ethyl acetate (15:1) to afford
46 (1.20 g, 67%) as a white solid. Mp 181–183 ꢁC; 1H NMR
4.7.11. (R)-(þ)-1-(2-Methoxy-1-naphthyl)-3-(2-furyl)-5,6,7,8-
tetrahydroisoquinoline (R)-(þ)-(42d)30b
Mp 198–199 ꢁC (acetone); [a 2D5
]
þ172.5 (c 0.31, CHCl3); 1H NMR
(CDCl3, 400 MHz)
d
8.19 (d, J¼8.9 Hz, 1H), 8.12–8.10 (m, 1H), 7.78 (br s,
2H), 7.64–7.59 (m, 3H), 7.54–7.5 (m,1H), 7.23 (d, J¼3.2 Hz,1H), 6.74–6.76
(m, 1H), 3.14 (s, 3H), 3.17–3.20 (m, 2H), 2.75–2.67 (m,1H), 2.46–2.38 (m,
1H), 2.1–1.88 (m, 4H); 13C NMR (CDCl3)
d 156.2, 154.7, 154.3, 147.2, 146.7,
143.0, 133.6, 132.4, 130.1, 129.7, 128.8, 128.3, 127.0, 125.1, 124.0, 118.6,
114.3, 112.1, 108.2, 57.2, 30.0, 26.0, 23.3, 22.8; MS (70 eV), m/z 355 (70)
[Mþ], 354 (100), 336 (43), 326 (25), 324 (27), 311 (20). Enantiomeric
purity by HPLC analysis >98% ee; HPLC conditions: Chiracel OD-H,
hexane/ethanol 99:1, 1.0 mL/min, t1¼5.76 min, t2¼7.94 min.
(400 MHz, CDCl3)
(m, 2H), 7.97–8.01 (m, 4H), 8.18–8.21 (m, 4H), 8.24 (s, 2H); 13C NMR
(100 MHz, CDCl3) 116.9 (CH), 127.1 (CH), 127.2 (CH), 127.3 (CH),
127.5 (CH), 128.5 (CH), 128.7 (CH), 130.3 (CH), 138.0 (C), 139.5 (C),
d 7.38–7.42 (m, 2H), 7.45–7.50 (m, 6H), 7.69–7.73
d
4.7.12. 3-Phenyl-2H-isoquinoline (44)
149.8 (C), 157.9 (C); IR (KBr) n 3047, (aryl C–H), 1619, 1590, 1558,
n-Butyllithium (2.5 M in hexane, 84 mL, 197 mmol) was added
to a solution of N-methyl-o-toluamide 43 (10.0 g, 67 mmol) in THF
(250 mL) at ꢂ20 ꢁC. The reaction mixture was stirred at the same
temperature for 2 h, then a solution of benzonitrile (11.7 mL,
109 mmol) in THF (20 mL) was added at ꢂ50 ꢁC and the mixture
was left stirred at room temperature for 18 h. The reaction was
quenched with water (40 mL) and the product was extracted into
CH2Cl2 (3ꢅ40 mL). The organic layers were combined, dried over
MgSO4 and evaporated. Crystallization of the residue from AcOEt
afforded 44 (5.3 g, 36%). Mp 203–205 ꢁC [lit.32 gives 205 ꢁC]; 1H
1496 (aromatic rings) cmꢂ1; CIMS m/z (%) 409 ([MþH]þ, 100), 206
(3), 113 (2), 85 (6), 69 (9); HRMS (CI) 409.1707 (C30H21N2 requires
409.1705).
4.7.15. 2-(Phenylacetylene)benzaldehyde (48)
(Ph3P)2PdCl2 (152 mg, 0.22 mmol) and CuI (21 mg, 0.11 mmol)
were added to a solution of 2-bromobenzaldehyde 47 (2.00 g,
10.81 mmol) and phenylacetylene (1.32 g, 12.97 mmol) in dry
triethylamine (45 mL). The resulting mixture was heated under an
argon atmosphere at 50 ꢁC for 2 h and then allowed to cool to room
temperature. The ammonium salt formed was removed by filtra-
tion and the filtrate was concentrated under reduced pressure and
NMR (CDCl3, 400 MHz)
d 6.80 (s, 1H), 7.49–7.78 (m, 8H), 8.40 (d,
J¼7.5 Hz, 1H), 10.54 (s, 1H) in agreement with the literature data.32

A.V. Malkov et al. / Tetrahedron 64 (2008) 11335–11348
11347
purified by flash chromatography on a column of silica gel (125 g)
with a mixture of petroleum ether and ethyl acetate (24:1) to give
0.2 mmol), and aldehyde 1 (0.2 mmol) in solvent (2 mL) under ni-
trogen at the required temperature (Table 2). The mixture was then
stirred at this temperature until completion (by TLC monitoring)
and then quenched with aqueous satd NaHCO3 (5 mL). The aqueous
layer was extracted with CH2Cl2 (3ꢅ5 mL) and the combined
organic layers were washed with brine, dried over MgSO4, and the
solvent was removed in vacuo. Products 3 were either identical
with the authentic sample8–11 or their NMR data corresponded
to those published; for their full characterization, see our earlier
papers.8–11
48 (2.20 g, 99%) as a yellow oil. 1H NMR (CDCl3, 400 MHz)
d 7.40–
7.45 (m, 3H), 7.49 (t, J¼7.5 Hz,1H), 7.59–7.65 (m, 3H), 7.69 (dd, J¼7.7,
1.2 Hz, 1H), 7.99 (dd, J¼7.8, 1.3 Hz, 1H), 10.69 (s, 1H); 13C NMR
d 85.0
(Csp), 96.4 (Csp), 122.4 (C), 126.9 (C), 127.3 (CH), 128.5 (CH), 128.7
(CH), 129.1 (CH), 131.7 (CH), 133.3 (CH), 133.8 (CH), 135.8 (C), 191.6
(CH) in agreement with the reported data.37
4.7.16. t-Butyl-(2-phenylethynyl-benzylidine)-amine (49)
A solution of 48 (1.96 g, 9.50 mmol, 1.0 equiv) in tert-butylamine
(6.0 mL, 57.02 mmol, 6.0 equiv) was stirred under an Ar atmo-
sphere at room temperature for 24 h. The resultant mixture was
extracted with ether (3ꢅ30 mL) and the combined organic extracts
were dried over MgSO4, and concentrated under reduced pressure
to give 49 (2.32 g, 94%) as a crystalline yellow solid. Mp 54–56 ꢁC;
Acknowledgements
We thank Schering-Plough (formerly Organon) for a fully-fun-
ded studentship to MMW, the Ministry of Education and Science of
Spain for a fellowship to PR-L, the Socrates-Erasmus exchange
program for a fellowship to A.K., the Czech Science Foundation for
Grant No. 203/08/0350, the Ministry of Education of the Czech
Republic (Project No. LC06070, MSM0021620857 and MSM-
6046137301), and the University of Glasgow and Dr. Alfred Bader
for additional support.
1H NMR (CDCl3, 400 MHz)
d 1.27 (s, 9H), 7.27–7.34 (m, 5H), 7.44–
7.50 (m, 3H), 7.99 (dd, J¼5.7, 3.6 Hz, 1H), 8.86 (s, 1H); 13C NMR
(CDCl3, 100 MHz)
d 28.7 (CH3), 56.8 (CMe3), 85.7 (Csp), 93.8 (Csp),
122.0 (C), 122.8 (C), 124.9 (CH), 127.5 (CH), 127.5 (CH), 127.6 (CH),
128.7 (CH), 130.4 (CH), 131.2 (CH), 136.8 (C), 153.2 (CH) in agree-
ment with the published data.38
References and notes
4.7.17. 3-Phenylisoquinoline (50)
Copper(I) iodide (185 mg, 0.97 mmol, 0.1 equiv) was added to
a solution of imine 49 (2.54 g, 9.72 mmol, 1.0 equiv) in DMF (20 mL)
and the mixture was heated to 100 ꢁC for 4 h. The mixture was then
allowed to reach room temperature, diluted with ether, and
washed with saturated ammonium chloride solution (2ꢅ35 mL).
The organic layer was dried over MgSO4 and concentrated under
reduced pressure. The crude residue was purified by flash chro-
matography on a column of silica gel (100 g) with a mixture of
petroleum ether and ethyl acetate (20:1) to afford 50 (1.72 g, 86%)
ˇ
´
1. Kocovsky, P.; Malkov, A. V. Chiral Lewis Bases as Catalysts. In Enantioselective
Organocatalysis; Dalko, P. I., Ed.; Wiley-VCH: Weinheim, 2007; p 255.
2. (a) Denmark, S. E.; Stavenger, R. A. Acc. Chem. Res. 2000, 33, 432; (b) Denmark,
S. E.; Fu, J. Chem. Commun. 2003, 167; (c) Denmark, S. E.; Fu, J. Chem. Rev. 2003,
103, 2763; (d) Denmark, S. E.; Fu, J. Tetrahedron: Asymmetry 2006, 17, 687; (e)
Denmark, S. E.; Beutner, G. L. Angew. Chem., Int. Ed. 2008, 47, 1560.
ˇ
´
3. For a recent overview, see the following: Malkov, A. V.; Kocovsky, P. Eur. J. Org.
Chem. 2007, 29.
4. (a) Nakajima, M.; Saito, M.; Shiro, M.; Hashimoto, S. J. Am. Chem. Soc. 1998, 120,
6419; (b) Nakajima, M.; Saito, M.; Hashimoto, S. Chem. Pharm. Bull. 2000, 48,
306.
5. (a) Shimada, T.; Kina, A.; Ikeda, S.; Hayashi, T. Org. Lett. 2002, 4, 2799; (b)
Shimada, T.; Kina, A.; Hayashi, T. J. Org. Chem. 2003, 68, 6329; (c) Kina, A.;
Shimada, T.; Hayashi, T. Adv. Synth. Catal. 2004, 346, 1169.
6. For an analogous trioxide, see the following: Wong, W.-L.; Lee, C.-S.; Leung,
H.-K.; Kwong, H.-L. Org. Biomol. Chem. 2004, 2, 1967.
7. (a) Hrdina, R.; Kadlcıkova, A.; Valterova, I.; Hodacova, J.; Kotora, M. Tetrahedron:
Asymmetry 2007, 17, 3185; (b) Hrdina, R.; Stara´, I. G.; Dufkova´, L.; Mitchell, S.;
Cısarova, I.; Kotora, M. Tetrahedron 2006, 62, 968; (c) Hrdina, R.; Valterova, I.;
Hodacova, J.; Kotora, M. Adv. Synth. Catal. 2007, 349, 822; (d) Hrdina, R.; Dra-
cinsky, M.; Valterova, I.; Hodacova, J.; Cısarova, I.; Kotora,, M. Adv. Synth. Catal.
2008, 350, 1449.
as a beige solid. Mp 102–103 ꢁC; 1H NMR (CDCl3, 400 MHz)
d
7.35
(tt, J¼7.4, 1.2 Hz, 1H), 7.41–7.47 (m, 2H), 7.51 (ddd, J¼8.0, 6.9, 1.0 Hz,
1H), 7.62 (ddd, J¼8.1, 6.9, 1.2 Hz, 1H), 7.80 (d, J¼8.1 Hz, 1H), 7.92 (d,
J¼8.1 Hz, 1H), 8.00 (s, 1H), 8.04–8.08 (m, 2H), 9.27 (s, 1H); 13C NMR
ˇ´
´
´
ˇ
´
(CDCl3, 100 MHz)
d 116.5 (CH), 126.9 (CH), 127.0 (CH), 127.1 (CH),
127.6 (CH), 127.8 (C), 128.5 (2ꢅCH), 128.8 (2ꢅCH), 130.5 (CH), 136.7
(C), 139.6 (C), 151.3 (C), 152.4 (CH), in agreement with the published
data.39
´
ˇ
´
´
ˇ
´
ˇ
´
ˇ
´
´
ˇ
´
8. (a) Malkov, A. V.; Orsini, M.; Pernazza, D.; Muir, K. W.; Langer, V.; Meghani, P.;
4.7.18. 3-Phenylisoquinoline N-oxide (51)
ˇ
´
Kocovsky, P. Org. Lett. 2002, 4, 1047; (b) Malkov, A. V.; Bell, M.; Orsini, M.;
ˇ
´
Pernazza, D.; Massa, A.; Herrmann, P.; Meghani, P.; Kocovsky, P. J. Org. Chem.
2003, 68, 9659.
m-CPBA (2.42 g, 14.04 mmol, 2.0 equiv) was added to a pre-
cooled (0 ꢁC) solution of 50 (1.44 g, 7.02 mmol, 1.0 equiv) in CH2Cl2
(15 mL) and the reaction was then allowed to reach room tem-
perature and stirred for 4 h. The resulting mixture was diluted with
CH2Cl2 (25 mL) and water (25 mL), the layers were separated and
the aqueous phase was extracted with CH2Cl2 (2ꢅ25 mL). Com-
bined organic extracts were washed with 10% aqueous sodium
carbonate (2ꢅ25 mL), dried over MgSO4, and concentrated under
reduced pressure. The crude residue was purified by flash chro-
matography on a column of silica gel (100 g), first with ethyl acetate
to elute impurities, followed by a mixture of ethyl acetate and
methanol (10:1) to furnish 51 (1.16 g, 75%) as a white solid. Mp 159–
ˇ
´
9. Malkov, A. V.; Bell, M.; Vassieu, M.; Bugatti, V.; Kocovsky, P. J. Mol. Catal. A 2003,
196, 179.
´
ˇ
´
10. (a) Malkov, A. V.; Dufkova, L.; Farrugia, L.; Kocovsky, P. Angew. Chem., Int. Ed.
2003, 42, 3674; (b) Malkov, A. V.; Ramı´rez-Lo´ pez, P.; Biedermannova, L.;
ˇ
´
Rulisek, L.; Dufkova, L.; Kotora, M.; Zhu, F.; Kocovsky, P. J. Am. Chem. Soc.
2008, 130, 5341.
ˇ
´
11. Malkov, A. V.; Bell, M.; Castelluzzo, F.; Kocovsky, P. Org. Lett. 2005, 7, 3219.
12. For other N-oxides, see the following: (a) Traverse, J. F.; Zhao, Y.; Hoveyda, A. H.;
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13. (a) Malkov, A. V.; Bella, M.; Langer, V.; Kocovsky, P. Org. Lett. 2000, 2, 3047; (b)
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Malkov, A. V.; Pernazza, D.; Bell, M.; Bella, M.; Massa, A.; Teply´, F.; Meghani, P.;
ˇ
´
160 ꢁC; 1H NMR (CDCl3, 400 MHz)
d 7.49–7.56 (m, 3H), 7.61–7.66
ˇ
´
Kocovsky, P. J. Org. Chem. 2003, 68, 4727.
(m, 2H), 7.78 (d, J¼9.2 Hz, 1H), 7.83–7.86 (m, 4H), 9.00 (s, 1H); 13C
14. Brown, H. C.; Weissman, S. A.; Perumal, P. T.; Dhokte, U. P. J. Org. Chem. 1990, 55,
1217.
NMR (CDCl3, 400 MHz)
d 124.5 (CH), 124.8 (CH), 126.6 (CH), 128.3
15. Gianini, M.; von Zelewsky, A. Synthesis 1996, 702.
(CH), 128.9 (CH), 129.0 (C), 129.1 (CH), 129.3 (C), 129.4 (CH), 129.8
(CH), 132.9 (C), 137.1 (CH), 147.1 (C) in agreement with the literature
data.40
16. Mihelich, E. D.; Eickhoff, D. J. J. Org. Chem. 1983, 48, 4135.
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4.8. General procedure for the allylation reaction
ˇ
´
Kocovsky, P. Curr. Org. Chem. 2003, 7, 1737.
Allyltrichlorosilane 2 (40
of the catalyst (1–10 mol %), diisopropylethylamine (34
m
L, 0.28 mmol) was added to a solution
L,
19. Lo¨tscher, D.; Rupprecht, S.; Stoeckli-Evans, H.; von Zelewsky, A. Tetrahedron:
Asymmetry 2000, 11, 4341.
m

11348
A.V. Malkov et al. / Tetrahedron 64 (2008) 11335–11348
20. The high diastereoselectivity originates from the steric hindrance of the top
face by the geminal dimethyl group.13,18
21. For the method, see: Teague, P. C.; Ballentine, A. R.; Rushton, G. L. J. Am. Chem.
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34. For the method of a-chloropyridine dimerization, see Refs. 8 and 13 and the
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Dehmlow, E. V.; Sleegers, A. Liebigs Ann. Chem. 1992, 9, 953; (c) Brenner, E.;
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B.; Rafikov, S. R. Tetrahedron Lett. 1971, 12, 2807.
35. For an inspiration, see: a different approach to 46, in which we attempted to
dimerize 1,3-dichloroisoquinoline (coupling at the more reactive 1-position),
followed by the Suzuki-type phenylation of the 3,30-dichloro groups, was un-
successful owing to the polymerization of the starting material in the first step.
Ford, A.; Sinn, E.; Woodward, S. J. Chem. Soc., Perkin Trans. 1 1997, 927.
36. For the method, see the following: Campeau, L.-C.; Rousseaux, S.; Fagnou, K. J.
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also: (c) Takao, S.; Yoshinori, K.; Masafumi, S.; Hiroshi, Y. Synthesis 1984, 3, 245.
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10063.
25. Lambert, J. B.; Ziemnicka-Merchant, B. T.; Hayden, M. A.; Hjelmfelt, A. T. J. Chem.
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the method of acid-mediated hydrolysis, see: (b) Stanton, J. L.; Gruenfeld, N.;
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ˇ
ˇ
ˇ
ˇ
´
41. (a) Smrcina, M.; Lorenc, M.; Hanus, V.; Sedmera, P.; Kocovsky, P. J. Org. Chem.
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´
ˇ
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1992, 57, 1917; (b) Smrcina, M.; Polakova, J.; Vyskocil, S.; Kocovsky, P. J. Org.
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43. In principle, coordination of two molecules of the N-monooxide might be
considered, which could result in a similar boost in the reactivity of 2. However,
this option is unlikely since the reaction order in the closely related analogue
11 was shown to be unity.10b
44. The correlation cannot be extended to the closest analogue (S)-(ꢂ)-17a since
Nakajima only reported the enantioselectivity attained but not the absolute
configuration of the product 2.4a
31. For the method, see: Cho, W.-J.; Kim, E.-K.; Park, I. Y.; Jeong, E. Y.; Kim, T. S.; Le,
T. N.; Kim, D.-D.; Lee, E.-S. Bioorg. Med. Chem. 2002, 10, 2953.
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45. Case, F. H.; Kasper, T. J. J. Am. Chem. Soc. 1956, 78, 5842.