Organocatalytic asymmetric 1,4-addition of aldehydes to acridiniums catalyzed by a diarylprolinol silyl ether

Article abstract of DOI:10.1021/jo2025114

The organocatalytic enantioselective 1,4-addition of aldehydes to acridiniums catalyzed by diarylprolinol silyl ether was achieved to furnish chiral acridanes in both high yields (82-96%) and excellent enantioselectivities (up to 99% ee), which also provides the highly enantioselective intermolecular α-alkylation of aldehydes with acridiniums salt.

Full text of DOI:10.1021/jo2025114

Note
pubs.acs.org/joc
Organocatalytic Asymmetric 1,4-Addition of Aldehydes to
Acridiniums Catalyzed by a Diarylprolinol Silyl Ether
Tao Liang,†,‡ Jian Xiao,*,† Zhiyi Xiong,† and Xingwei Li*,†
†Dalian Institute of Chemical Physics, The Chinese Academy of Sciences, Dalian, 116023, P. R. China
‡Key Laboratory of Bio-based Material Science and Technology of Ministry of Education, Northeast Forestry University, Harbin
150040, P. R. China
S
* Supporting Information
ABSTRACT: The organocatalytic enantioselective 1,4-addi-
tion of aldehydes to acridiniums catalyzed by diarylprolinol
silyl ether was achieved to furnish chiral acridanes in both high
yields (82−96%) and excellent enantioselectivities (up to 99%
ee), which also provides the highly enantioselective
intermolecular α-alkylation of aldehydes with acridiniums salt.
zaaromatics are an important class of compounds in drug
industry and in natural product synthesis.1 Activation of
Scheme 1. Reactions of Aldehydes and Azaaromatics
A
nitrogen-containing aromatics toward nucleophilic addition by
means of N-acylation, N-alkylation, and N-oxidation constitutes
one of the most important and general strategies to construct
new C−C bonds in heterocyclic chemistry.2 Nevertheless, only
limited asymmetric systems have been reported despite their
significance in the synthesis of biologically active and
enantioenriched azacycles.3 Of all these 1,2-addition reactions
of nucleophiles to nitrogen-containing heterocycles, the
organocatalytic strategy is highly attractive owing to the
thermal and moisture robustness and mild conditions.4 As a
well-known class of nucleophile in asymmetric catalysis,
enamines4a can conceivably attack the covalently preactivated
azaaromatics (such as quinoliniums and isoquinoliniums),
producing optically active carbonyl-functionalized 1,2-dihydro-
quinolines and 1,2-dihydroisoquinolines, which can be further
chemically manipulated. Despite the importance, this type of
reaction is rather rare. Although Jørgensen reported the sole
example of highly enantioselective organocatalytic intramolec-
ular 1,2 addition of aldehydes to isoquinolinium ions in 2005,5
the corresponding intermolecular version is unsuccessful
(Scheme 1a,b). In contrast to the known 1,2 addition fashion,
the intermolecular 1,4 addition of aldehydes to acridiniums was
reported only recently.6a However, only low to moderate
enantioselectivities were observed and no such highly
enantioselective addition has been reported until now.6 In
our continuing efforts to develop new highly enantioselective
organocatalytic reactions,7 we herein report the highly
enantioselective intermolecular 1,4-addition of aldehydes to
acridiniums catalyzed by a chiral secondary amine (Scheme 1c).
It has been shown that diarylprolinol silyl ether (I) acts as a
highly efficient catalyst for the asymmetric α-functionalization
of aldehydes.8 Therefore, we started to explore the reaction of
aldehydes and N-methylquinolinium iodide in the presence of
catalyst I (10 mol %) and 1 equiv of 2,6-lutidine. However,
essentially no reaction occurred either at room temperature or
at 60 °C. Noting that acridine and acridane moieties are present
in natural products and are widely used as biological dyes,
fluorescent materials, and chiroptical molecular switches,9 we
turned our attention to the more reactive acridinium salts. The
reaction of N-methylacridinium iodide 2a and valeryl aldehyde
1c was conducted as the model reaction using 2,6-lutidine as a
base. To our delight, the desired product 3c was obtained in
89% yield and 86% ee in CH2Cl2 (Table 1, entry 1). A base
proved necessary to absorb the HI byproduct (Table 1, entry
2). Next, different bases were screened, and it was found that
commonly used organic bases such as pyridine and Et3N gave
the desired product in good yields and moderate to good
enantioselectivity (Table 1, entries 3−6). Gratifyingly, DMAP
afford the best result with 91% yield and 96% ee (Table 1, entry
7).10 In contrast, when inorganic bases were used, the product
was obtained in low yield, albeit with high enantioselectivity
(Table 1, entries 8 and 9). The low efficiency of these bases is
probably due to their poor solubility and low reactivity in
organic solvents. Screening of different solvents indicated that
Received: December 23, 2011
Published: March 5, 2012
© 2012 American Chemical Society
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Note
a
Table 1. Screening of the Catalyst and Base
b
c
entry
base
catalyst
solvent
yield (%)
ee (%)
1
2,6-lutidine
I
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
DCE
89
<5
86
2
I
3
pyridine
imidazole
Et3N
I
83
−61
30
48
88
96
94
97
97
96
94
92
97
4
I
86
5
I
67
6
acridine
DMAP
NaHCO3
Na2CO3
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
I
53
7
I
91
8
I
32
9
I
37
10
11
12
13
14
15
16
17
18
I
94
I
92
I
toluene
THF
78
I
67
I
dioxane
MeOH
DMF
96
I
trace
trace
trace
trace
79
I
I
DMSO
H2O
I
d
19
I
dioxane
dioxane
dioxane
dioxane
97
95
e
20
I
35
21
22
II
III
73
76
35
−5
a
Reactions were conducted with 1a (0.4 mmol), 2a (0.1 mmol), catalyst I (0.01 mmol), and base (0.1 mmol) in 1 mL of solvent at room
b
c
d
e
temperature. Isolated yield. ee was determined by HPLC analysis on a chiral stationary phase. 5 mol % of I was used. 1 mol % of I was used.
a
Table 2. Substrate Scope
b
c
entry
R1
R2
product
yield (%)
ee (%)
1
2
3
4
5
6
7
CH3
Me
Me
Me
Me
Me
Me
Me
Me
Et
3a
3b
3c
3d
3e
3f
90
86
96
91
93
93
92
83
82
84
85
94
96
98
95
97
97
90
86
89
95
99
C2H5
C3H7
C4H9
C6H13
C7H15
PhCH2
i-Pr
3g
3h
3i
d
8
9
10
11
C3H7
C3H7
C3H7
Pr
3j
Bu
3k
a
Reactions were conducted with aldehyde 1 (0.4 mmol), 2 (0.1 mmol), catalyst I (0.01 mmol), and DMAP (0.1 mmol) in 1 mL of dioxane at room
b
c
d
temperature. Isolated yield. ee was determined by HPLC analysis on a chiral stationary phase. Reaction time was 72 h.
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Note
halogenated solvents such as CHCl3 and ClCH2CH2Cl
consistently gave excellent yields and excellent enantioselectiv-
ities (Table 1, entries 10 and 11), while lower yields but high
enantioselectivity were obtained in toluene or THF (Table 1,
entries 12 and 13). Eventually, dioxane proved to be the
optimal solvent, in which product 3c was obtained in 96%
isolated yield and 97% ee (Table 1, entry 14). In addition, only
traces of products were detected when polar solvents such as
MeOH, DMF, DMSO, and water were used (Table 1, entries
15−18). Under the optimal conditions, when the catalyst
loading was decreased to 5 mol %, high yield and high
enantioselectivity could still be obtainable (Table 1, entry 19).
Using 1 mol % of catalyst loading resulted in lower chemical
yield but still high enantioselectivity (Table 1, entry 20). In
comparison, lower yield and lower enantioselectivity were
obtained for catalyst II (Table 1, entry 21), highlighting the
importance of substituted trifluoromethyl group for this
reaction, which not only affects the enantioselectivity but also
the reactivity. In contrast, the well-known MacMillan catalyst
(III)11 afforded the desired product 3c only in 35% yield and
5% ee (Table 1, entry 22).
A plausible mechanism for the formation of 3 is given in
Scheme 3. Reaction of aldehyde 1 with chiral secondary amine
Scheme 3. Proposed Catalytic Cycle
Various aldehydes were allowed to react with N-methyl-
acridinium iodide to define the scope of aldehydes. Gratifyingly,
in all cases, the desired products were obtained in high yields
(83−96%) and excellent enantioselectivities (86−98% ee),
making this methodology highly valuable. Not only linear
aldehydes, but also branched aldehydes such as isovaleryl
aldehyde, are applicable (Table 2, entries 1−8). Various
alkylated salts could also be tolerated without loss of any
efficiency or stereoselectivity (Table 2, entries 9−11).
catalyst I forms the (E)-enamine 7, which attacks the
acridinium salt 2 from the Si face to afford intermediate 8
since the Re face was efficiently shielded by the bulky silyl ether
group. Hydrolysis of 8 afforded product 3 together with the
regeneration of the catalyst I. The released HI was scavenged
by DMAP. Screening experimentation indicated that DMAP is
crucial in both reactivity and enantioselectivity. We believe that
in addition to acting as an acid scavenger, DMAP helps to form
a well-organized transition state during the attack of the
enamine 7 to the acridinium salt 2. In connection with the
significant effect of trifluoromethyl group in catalyst I, it is
possible that electrostatic interactions among the enamine,
acridinium salt, DMAP, and trifluoromethyl-substituted ar-
omatic ring were involved to stabilize the transition state.
In summary, we have developed an organocatalytic
enantioselective intermolecular 1,4-addition of aldehydes to
acridinium salts catalyzed by a chiral secondary amine. This
methodology provides the general protocol toward the highly
enantioenriched chiral acridane and tropylium derivatives, thus
overcoming the lack of which in the past. The high yields and
Further expansion of the substrate scope by moving to N-
methyl phenanthridinium iodide (4) failed even when the
mixture was heated at 60 °C (Scheme 2). This indicates that 1,
Scheme 2. Substrate Scope
2 addition failed to proceed in this system. However, when we
extended the electrophile to the commercially available and air
stable tropylium hexafluorophosphate 5, successful reaction was
achieved under the standard conditions to give the desired
products 6a−e in comparably high yields and excellent
enantioselectivities (91−99% ee, Table 3).
a
Table 3. Substrate Scope
b
c
entry
R
product
yield (%)
ee (%)
1
2
3
4
5
CH3
6a
6b
6c
6d
6e
85
83
80
81
71
95
91
99
97
97
C2H5
C3H7
C4H9
PhCH2
a
Reactions were conducted with aldehyde 1 (0.4 mmol), 2 (0.1 mmol), catalyst I (0.01 mmol), and DMAP (0.1 mmol) in 1 mL of dioxane at room
b
c
temperature. Isolated yield. ee was determined by HPLC analysis on a chiral stationary phase.
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Note
1H), 3.62 (s, 1H), 3.48 (dd, J = 11.1, 5.5 Hz, 1H), 3.41−3.37 (dd, J =
11.1, 4.2 Hz 1H), 3.36 (s, 3H), 1.77−1.54 (m, 2H), 1.54−0.88 (m,
6H), 0.79 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 143.2,
143.1, 129.1, 128.7, 127.0, 126.8, 126.4, 126.2, 120.5, 120.4, 112.1,
112.0, 62.3, 46.4, 44.8, 32.9, 29.3, 27.4, 22.9, 13.9; HRMS (ESI) calcd
for C20H26NO 296.2014 [M + H]+, found 296.2015 [M + H]+.
(R)-2-(10-Methyl-9,10-dihydroacridin-9-yl)octan-1-ol (3e):
excellent enantioselectivities in this reaction make this method-
ology highly attractive in the synthesis of optically pure useful
acridane derivatives. This open air, room temperature reaction
without resort to any dry solvent or reagent is quite promising
for future applications. Furthermore, the success of this reaction
provides the rare highly enantioselective example for the
asymmetric intermolecular α-alkylation of aldehydes.12
1
colorless oil; 30 mg, 0.093 mmol, yield 93%; H NMR (CDCl3, 400
MHz) δ 7.36−7.20 (m, 4H), 7.08−6.96 (m, 4H), 4.08 (d, J = 7.2 Hz,
1H), 3.56 (dd, J = 11.2, 5.4 Hz, 1H), 3.47 (dd, J = 11.2, 4.2 Hz, 1H),
3.45 (s, 3H), 1.71 (m, 1H), 1.58−1.11 (m, 10H), 0.93 (t, J = 7.1 Hz,
3H); 13C NMR (CDCl3, 125 MHz) δ 143.2, 143.2, 129.1, 128.7,
127.0, 126.9, 126.4, 126.3, 120.6, 120.5, 112.1, 112.1, 62.5, 46.5, 44.9,
32.9, 31.7, 29.5, 27.7, 27.1, 22.6, 14.0; HRMS (ESI) calcd for
C22H30NO 324.2327 [M + H]+, found 324.2330 [M + H]+.
EXPERIMENTAL SECTION
■
General Methods. All reagents were purchased from commercial
sources and were used as received, unless otherwise indicated. 1H
NMR and 13C NMR were recorded in CDCl3. H NMR spectra are
1
reported as δ in units of parts per million (ppm) downfield from SiMe4
(δ 0.0) and relative to the signal of chloroform-d (δ 7.2600, singlet).
13C NMR are reported as δ in units of parts per million (ppm)
downfield from SiMe4 (δ 0.0) and relative to the signal of chloroform-
d (δ 77.0, triplet). Enantioselectivities were determined by HPLC
analysis employing a chiral column at 25 °C. Optical rotation was
measured using a polarimeter equipped with a sodium vapor lamp at
589 nm. Concentration is denoted as c and was calculated as grams per
deciliters (g/100 mL).
(R)-2-(10-Methyl-9,10-dihydroacridin-9-yl)nonan-1-ol (3f):
1
colorless oil; 31.4 mg, 0.093 mmol, yield 93%; H NMR (CDCl3,
400 MHz) δ 7.39−7.18 (m, 4H), 7.14−6.90 (m, 4H), 4.08 (d, J = 7.2
Hz, 1H), 3.56 (dd, J = 11.2, 5.5 Hz, 1H), 3.50−3.45 (dd, J = 11.2, 4.2
Hz, 1H), 3.45 (s, 3H), 1.72 (m, 1H), 1.45−1.12 (m, 12H), 0.94 (t, J =
7.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 143.2, 143.1, 129.1,
128.7, 127.0, 126.8, 126.4, 126.2, 120.5, 120.4, 112.1, 112.0, 62.4, 46.4,
44.8, 32.9, 31.8, 29.5, 29.1, 27.6, 27.1, 22.6, 14.1; HRMS (ESI) calcd
for C23H32NO 338.2484 [M + H]+, found 338.2484 [M + H]+.
(R)-2-(10-Methyl-9,10-dihydroacridin-9-yl)-3-phenylpropan-
General Procedure for the Enantioselective 1,4-Addition of
Aldehydes to Acridinium Salts. To a solution of acridinium salt 2
(0.1 mmol) and catalyst I (0.01 mmol) in dioxane (1 mL) was added
propyl aldehyde (0.4 mmol). The resulting solution was stirred at
room temperature for 24 h. Upon the completion of reaction as
monitored by TLC, EtOH (1 mL) was added. NaBH4 was then
cautiously added to the solution, which was stirred at room
temperature for 0.5 h. The reaction was subsequently quenched with
saturated NH4Cl solution. The aqueous solution was extracted with
ethyl acetate (2 mL × 3). The combined organic phases were washed
with brine and dried over anhydrous MgSO4. The solvent was
removed under reduced pressure, and the resulting yellow oil was
purified by preparative chromatography or column chromatography
(hexane/ethyl acetate = 10/1) to afford the desired product 3a as a
colorless oil (22.8 mg, 90% yield). The enantiomeric excess was
determined by HPLC analysis using a chiral AD-H column. The
absolute configuration was determined by comparison of optical
rotations with those reported products in the literature (ref 6a).
(R)-2-(10-Methyl-9,10-dihydroacridin-9-yl)propan-1-ol (3a):
colorless oil; 22.8 mg, 0.090 mmol, yield 90%; 1H NMR (CDCl3,
500 MHz) δ 7.26−7.12 (m, 4H), 6.98−6.88 (m, 4H), 3.91 (d, J = 7.1
Hz, 1H), 3.48 (dd, J = 10.8, 5.8 Hz, 1H), 3.36 (s, 3H), 3.34 (dd, J =
10.9, 5.7 Hz, 1H), 1.83 (m, 1H), 0.75 (d, J = 6.9 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) δ 143.1, 143.0, 129.2, 128.6, 127.0, 126.9, 126.4,
125.5, 120.5, 120.3, 112.1, 112.04, 65.3, 45.9, 41.6, 32.9, 14.0; HRMS
(ESI) calcd for C17H20NO 254.1545 [M + H]+, found 254.1550 [M +
H]+.
(R)-2-(10-Methyl-9,10-dihydroacridin-9-yl)butan-1-ol (3b).
colorless oil; 23.0 mg, 0.086 mmol, yield 86%; 1H NMR (CDCl3,
500 MHz) δ 7.27−7.13 (m, 4H), 6.99−6.88 (m, 4H), 4.01 (d, J = 7.4
Hz, 1H), 3.50 (dd, J = 11.1, 5.4 Hz, 1H), 3.42 (dd, J = 11.2, 4.1 Hz,
1H), 3.37 (s, 3H), 1.62−1.53 (m, 1H), 1.40−1.20 (m, 2H), 0.82 (t, J =
7.4 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 143.2, 143.2, 129.1,
128.7, 127.0, 126.8, 126.3, 126.3, 120.5, 120.4, 112.1, 112.1, 61.7, 47.8,
44.7, 32.9, 20.4, 11.7; HRMS (ESI) calcd for C18H22NO 268.1701 [M
+ H]+, found 268.1702 [M + H]+.
(R)-2-(10-Methyl-9,10-dihydroacridin-9-yl)pentan-1-ol (3c):
colorless oil; 27.0 mg, 0.096 mmol, yield 96%; 1H NMR (CDCl3,
500 MHz) δ 7.34−7.10 (m, 4H), 7.04−6.84 (m, 4H), 4.00 (d, J = 7.2
Hz, 1H), 3.48 (dd, J = 11.2, 5.5 Hz, 1H), 3.42−3.37 (dd, J = 11.2, 4.2
Hz, 1H), 3.37 (s, 3H), 1.75−1.61 (m, 1H), 1.29−1.22 (m, 2H), 1.16−
1.02 (m, 2H), 0.78 (t, J = 7.1 Hz, 3H); 13C NMR (CDCl3, 100 MHz)
δ 143.2, 143.2, 129.1, 128.7, 127.0, 126.8, 126.4, 126.2, 120.6, 120.5,
112.1, 112.1, 62.3, 46.2, 44.9, 32.9, 30.0, 20.3, 14.3; HRMS (ESI) calcd
for C19H24NO 282.1858 [M + H]+, found 282.1860 [M + H]+.
(R)-2-(10-Methyl-9,10-dihydroacridin-9-yl)hexan-1-ol (3d):
colorless oil; 26.9 mg, 0.091 mmol, yield 91%; 1H NMR (CDCl3,
500 MHz) δ 7.20 (m, 4H), 6.99−6.88 (m, 4H), 4.00 (d, J = 7.2 Hz,
1
1-ol (3g): colorless oil; 30.3 mg, 0.092 mmol, yield 92%; H NMR
(CDCl3, 400 MHz) δ 7.43−6.82 (m, 13H), 4.16 (d, J = 6.9 Hz, 1H),
3.38 (s, 3H), 3.34 (dd, J = 6.7, 4.9 Hz, 2H), 2.66 (dd, J = 13.8, 4.7 Hz,
1H), 2.43 (dd, J = 13.8, 10.5 Hz, 1H), 2.01 (dd, J = 10.7, 5.5 Hz, 1H);
13C NMR (CDCl3, 100 MHz) δ 143.2, 140.9, 129.3, 128.9, 128.7,
128.4, 128.3, 127.1, 127.1, 126.1, 125.7, 125.7, 120.7, 120.5, 112.2,
112.2, 61.2, 48.9, 44.4, 34.0, 33.0; HRMS (ESI) calcd for C23H24NO
330.1858 [M + H]+, found 330.1857 [M + H]+.
(R)-3-Methyl-2-(10-methyl-9,10-dihydroacridin-9-yl)butan-
1
1-ol (3h): yellow oil; 23.3 mg, 0.083 mmol, yield 83%; H NMR
(CDCl3, 400 MHz) δ 7.22 (m, 4H), 7.02−6.84 (m, 4H), 4.02 (d, J =
8.5 Hz, 1H), 3.68−3.44 (m, 2H), 3.37 (d, J = 5.3 Hz, 3H), 1.74 (m,
1H), 1.51 (m, 1H), 0.94−0.84 (m, 6H); 13C NMR (CDCl3, 100 MHz)
δ 143.4, 143.0, 128.8, 128.0, 127.2, 127.0, 126.8, 126.3, 120.9, 120.5,
112.3, 112.1, 61.3, 51.0, 44.7, 32.9, 26.2, 22.3, 17.2; HRMS (ESI) calcd
for C19H24NO 282.1858 [M + H]+, found 282.1858 [M + H]+.
(R)-2-(10-Ethyl-9,10-dihydroacridin-9-yl)pentan-1-ol (3i): col-
1
orless oil; 24.2 mg, 0.082 mmol, yield 82%; H NMR (CDCl3, 400
MHz) δ 7.24 (m, 4H), 7.11−6.88 (m, 4H), 4.10 (d, J = 6.1 Hz, 1H),
4.04 (q, J = 7.0 Hz, 2H), 3.50 (dd, J = 11.1, 6.0 Hz, 1H), 3.42 (dd, J =
11.1, 4.4 Hz, 1H), 1.43 (t, J = 7.0 Hz, 3H), 1.24(m, 5H), 0.82 (t, J =
6.7 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 141.5, 141.4, 129.4,
129.0, 126.9, 126.8, 125.5, 125.5, 120.2, 120.1, 112.2, 112.2, 62.3, 48.1,
43.9, 39.7, 29.6, 20.4, 14.2, 11.5; HRMS (ESI) calcd for C20H26NO
296.2014 [M + H]+, found 296.2017 [M + H]+.
(R)-2-(10-Propyl-9,10-dihydroacridin-9-yl)pentan-1-ol (3j):
1
colorless oil; 26.0 mg, 0.084 mmol, yield 84%; H NMR (CDCl3,
400 MHz) δ 7.30−7.08 (m, 4H), 6.92 (m, 4H), 4.02 (d, J = 6.5 Hz,
1H), 3.81 (dd, J = 9.1, 6.8 Hz, 2H), 3.46 (dd, J = 11.1, 5.9 Hz, 1H),
3.38 (dd, J = 11.2, 4.3 Hz, 1H), 2.02−1.74 (m, 2H), 1.35−1.07 (m,
5H), 1.04 (t, J = 7.4 Hz, 3H), 0.76 (t, J = 6.9 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) δ 141.8, 141.8, 129.4, 129.0, 126.9, 126.8, 125.7,
125.6, 120.2, 120.1, 112.4, 112.4, 62.3, 47.8, 47.3, 44.2, 29.7, 20.4, 19.1,
14.2, 11.4; HRMS (ESI) calcd for C21H28NO 310.2171 [M + H]+,
found 310.2174 [M + H]+.
(R)-2-(10-Butyl-9,10-dihydroacridin-9-yl)pentan-1-ol (3k):
1
colorless oil; 27.5 mg, yield 0.085 mmol, 85%; H NMR (CDCl3,
400 MHz) δ 7.32−7.07 (m, 4H), 6.92 (t, J = 9.2 Hz, 4H), 4.02 (d, J =
6.4 Hz, 1H), 3.95−3.77 (m, 2H), 3.45 (dd, J = 11.0, 5.9 Hz, 1H), 3.38
(dd, J = 11.1, 4.1 Hz, 1H), 1.97−1.71 (m, 2H), 1.54−1.38 (m, 2H),
1.35−1.05 (m, 5H), 1.01 (t, J = 7.3 Hz, 3H), 0.76 (t, J = 6.8 Hz, 3H);
13C NMR (CDCl3, 100 MHz) δ 141.8, 141.8, 129.4, 129.0, 126.9,
126.8, 125.7, 125.6, 120.2, 120.1, 112.3, 112.3, 62.3, 47.8, 45.2, 44.2,
29.7, 27.8, 20.4, 20.4, 14.2, 13.8; HRMS (ESI) calcd for C22H30NO
324.2327 [M + H]+, found 324.2324 [M + H]+.
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Note
(R)-2-((2Z,4Z,6Z)-Cyclohepta-2,4,6-trienyl)propan-1-ol (6a):
colorless oil; 12.8 mg, 0.085 mmol, yield 85%; 1H NMR (CDCl3,
400 MHz) δ 6.72−6.61 (m, 2H), 6.38−6.14 (m, 2H), 5.30 (dd, J =
14.9, 8.4 Hz, 2H), 3.77 (dd, J = 10.8, 4.9 Hz, 1H), 3.60 (dd, J = 10.8,
6.5 Hz, 1H), 2.02 (m, 1H), 1.51 (m, 1H), 1.10 (d, J = 6.8 Hz, 3H);
13C NMR (CDCl3, 100 MHz) δ 130.9, 130.8, 125.0, 124.9, 124.0,
123.12, 66.5, 41.4, 37.3, 14.5; HRMS (ESI) calcd for C10H15O
151.1123 [M + H]+, found 151.1120 [M + H]+.
(2) For selected reviews, see: (a) Sliwa, W. Heterocycles 1986, 24,
181. (b) McEwen, W. E.; Cobb, R. L. Chem. Rev. 1955, 55, 511.
(c) Popp, F. D. Heterocycles 1973, 1, 165.
(3) Ahamed, M.; Todd, M. H. Eur. J. Org. Chem. 2010, 5935.
(4) For selected recent reviews for organocatalysis, see: (a) Mukher-
jee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471.
(b) Bertelsen, S.; Jørgensen, K. A. Chem. Soc. Rev. 2009, 38, 2178.
(c) MacMillan, D. W. C. Nature 2008, 455, 304. (d) Westermann, B.;
Ayaz, M.; Berkel, S. Angew. Chem., Int. Ed. 2010, 49, 846. (e) Grondal,
C.; Jeanty, M.; Enders, D. Nat. Chem. 2010, 2, 167. (f) Nielsen, M.;
Worgull, D.; Zweifel, T.; Gschwend, B.; Bertelsen, S.; Jørgensen, K. A.
Chem. Commun. 2011, 632.
(R)-2-((2Z,4Z,6Z)-Cyclohepta-2,4,6-trienyl)butan-1-ol (6b):
colorless oil; 13.6 mg, 0.083 mmol, yield 83%; 1H NMR (CDCl3,
400 MHz) δ 6.72−6.62 (m, 2H), 6.22 (m, 2H), 5.38−5.25 (m, 2H),
3.88−3.72 (m, 2H), 1.87−1.71 (m, 1H), 1.67 (m, 1H), 1.50 (m, 2H),
0.95 (t, J = 7.5 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 130.9, 130.7,
125.0, 124.9, 123.8, 123.7, 63.1, 43.6, 40.2, 21.3, 11.4; HRMS (ESI)
calcd for C11H17O 165.1279 [M + H]+, found 165.1280 [M + H]+.
(R)-2-((2Z,4Z,6Z)-Cyclohepta-2,4,6-trienyl)pentan-1-ol (6c):
(5) Frisch, K.; Landa, A.; Saaby, S.; Jørgensen, K. A. Angew. Chem.,
Int. Ed. 2005, 44, 6058.
(6) For a similar reaction with poor to modest ee, see: (a) Benfatti,
F.; Benedetto, E.; Cozzi, P. G. Chem. Asian J. 2010, 5, 2047. For
selected examples of organocatalytic Michael additions, see:
(b) Betancort, J. M.; Barbas, C. F. III Org. Lett. 2001, 3, 3737.
(c) Ramachary, D. B.; Prasad, M. S.; Madhavachary, R. Org. Biomol.
Chem. 2011, 9, 2715. (d) Zhu, S.; Yu, S.; Wang, Y.; Ma, D. Angew.
Chem., Int. Ed. 2010, 49, 4656. (e) Zhu, S.; Yu, S.; Ma, D. Angew.
Chem., Int. Ed. 2008, 47, 545. (f) Uehara, H.; Barbas, C. F. III Angew.
Chem., Int. Ed. 2009, 48, 9848.
(7) (a) Xiao, J. Org. Lett. 2012, DOI: 10.1021/ol3002859. (b) Xiao,
J.; Zhao, K.; Loh, T. P. Chem. Commun. 2012, 48, 3548. (c) Xiao, J.;
Zhao, K.; Loh, T. P. Chem. Asian J. 2011, 6, 2890. (d) Xiao, J.; Lu, Y.
P.; Liu, Y. L.; Wong, P. S.; Loh, T. P. Org. Lett. 2011, 13, 876. (e) Xiao,
J.; Xu, F. X.; Lu, Y. P.; Liu, Y. L.; Loh, T. P. Synthesis 2011, 1292.
(f) Xiao, J.; Xu, F. X.; Lu, Y. P.; Loh, T. P. Org. Lett. 2010, 12, 1220.
(8) For reviews, see: (a) Palomo, C.; Mielgo, A. Angew. Chem., Int.
Ed. 2006, 45, 7876. (b) Mielgo, A.; Palomo, C. Chem. Asian J. 2008, 3,
922. (c) Jensen, K. L.; Dickmeiss, G.; Jiang, H.; Albrecht, Ł.;
Jørgensen, K. A. Acc. Chem. Res. 2012, 45, 248. For the pioneering
work, see: (d) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew.
Chem., Int. Ed. 2005, 44, 4212. (e) Marigo, M.; Wabnitz, T. C.;
Fielenbach, D.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2005, 44, 794.
(f) Marigo, M.; Fielenbach, D.; Braunton, A.; Kjasgaard, A.; Jørgensen,
1
yellow oil; 14.3 mg, 0.080 mmol, yield 80%; H NMR (CDCl3, 400
MHz) δ 6.73 (m, 2H), 6.37−6.21 (m, 2H), 5.46−5.33 (m, 2H), 3.88−
3.80 (m, 2H), 1.99−1.84 (m, 1H), 1.67−1.30 (m, 5H), 1.01 (t, J = 7.1
Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 130.8, 130.7, 125.0, 124.9,
123.9, 123.8, 63.5, 41.9, 40.4, 31.0, 20.4, 14.4; HRMS (ESI) calcd for
C12H19O 179.1436 [M + H]+, found 179.1440 [M + H]+.
(R)-2-((2Z,4Z,6Z)-Cyclohepta-2,4,6-trienyl)hexan-1-ol (6d):
colorless oil; 15.6 mg, 0.081 mmol, yield 81%; 1H NMR (CDCl3,
400 MHz) δ 6.71−6.61 (m, 2H), 6.22 (m, 2H), 5.38−5.25 (m, 2H),
3.78 (m, 2H), 1.82 (m, 1H), 1.71−1.21 (m, 7H), 0.91 (t, J = 6.1 Hz,
3H); 13C NMR (CDCl3, 100 MHz) δ 130.8, 130.7, 125.0, 125.0,
123.9, 123.8, 63.6, 42.1, 40.5, 29.5, 28.4, 23.1, 14.0; HRMS (ESI) calcd
for C13H21O 193.1592 [M + H]+, found 193.1590 [M + H]+.
(R)-2-((2Z,4Z,6Z)-Cyclohepta-2,4,6-trienyl)-3-phenylpropan-
1
1-ol (6e): colorless oil; 16.1 mg, 0.071 mmol, yield 71%; H NMR
(CDCl3, 500 MHz) δ 7.23 (m, 5H), 6.67 (m, 2H), 6.33−6.13 (m,
2H), 5.39 (m, 2H), 3.79−3.60 (m, 2H), 2.96 (dd, J = 13.8, 4.5 Hz,
1H), 2.71 (dd, J = 13.8, 9.4 Hz, 1H), 2.18−2.04 (m, 1H), 1.76 (m,
1H); 13C NMR (CDCl3, 125 MHz) δ 140.5, 130.9, 130.8, 129.2,
128.4, 126.0, 125.2, 125.2, 123.7, 123.4, 62.5, 44.0, 40.2, 35.2; HRMS
(ESI) calcd for C16H19O 227.1436 [M + H]+, found 227.1440 [M +
H]+.
ASSOCIATED CONTENT
́
K. A. Angew. Chem., Int. Ed. 2005, 44, 3703. (g) Franzen, J.; Marigo,
M.; Fielenbach, D.; Wabnitz, T. C.; Kjærsgaard, A.; Jørgensen, A. K. J.
Am. Chem. Soc. 2005, 127, 18296.
■
S
* Supporting Information
1H, 13C NMR, and HPLC spectra for all compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(9) For representative examples, see: (a) Gonalves, M. S. T. Chem.
̨
Rev. 2009, 109, 190. (b) Troxler, T.; Hurth, K.; Mattes, H.; Prashad,
M.; Schoeffter, P.; Langenegger, D.; Enz, A.; Hoyer, D. Bioorg. Med.
Chem. Lett. 2009, 19, 1305. (c) Biwersi, J.; Tulk, B.; Verkman, A. S.
Anal. Biochem. 1994, 219, 139. (d) Mccapra, F. In The Chemistry of
Heterocyclic Compounds: Acridines; Acheson, R. M., Ed.; John Wiley &
Sons: New York, 1973; Vol. 9, p 615. (e) Guetzoyan, L.;
Ramiandrasoa, F.; Dorizon, H.; Desprez, C.; Bridoux, A.; Rogier, C.;
Pradines, B.; Perree-Fauvet, M. Bioorg. Med. Chem. 2007, 15, 3278.
(f) Denny, W. Curr. Med. Chem. 2002, 9, 1655.
AUTHOR INFORMATION
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Corresponding Author
*E-mail: xiaojian@dicp.ac.cn; xwli@dicp.ac.cn.
Notes
The authors declare no competing financial interest.
(10) For addition of DMAP to improve the efficiency, see:
(a) Sohtome, Y.; Tanatani, A.; Hashimoto, Y.; Nagasawa, K.
Tetrahedron Lett. 2004, 45, 5589. (b) Gu, L.; Zhao, G. Adv. Synth.
Catal. 2007, 349, 1629. (c) Zhang, X. J.; Liu, S. P.; Li, X. M.; Yan, M.;
Chan, A. S. C. Chem. Commun. 2009, 833. Also see ref 7e and 7f.
(11) (a) Lelais, G.; MacMillan, D. W. C. Aldrichimica Acta 2006, 39,
79. (b) Beeson, T. D.; Mastracchio, A.; Hong, J.-B.; Ashton, K.;
MacMillan, D. W. C. Science 2007, 316, 582. (c) Nicewicz, D. A.;
MacMillan, D. W. C. Science 2008, 322, 77.
(12) For reviews on asymmetric intermolecular α-alkylation of
aldehydes, see: (a) Melchiorre, P. Angew. Chem., Int. Ed. 2009, 48,
1360. (b) Alba, A.-N.; Viciano, M.; Rios, R. ChemCatChem 2009, 1,
437. (c) Tak-Tak, L.; Dhimane, H.; Dalko, P. I. Angew. Chem., Int. Ed.
2011, 50, 12146. For a review on asymmetric β-functionalization of
aldehydes, see: (d) Xiao, J. ChemCatChem 2012, DOI: 10.1002/
cctc.201100488.
ACKNOWLEDGMENTS
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We are grateful to the National Natural Science Foundation of
China (No. 21102142) and the Dalian Institute of Chemical
Physics, Chinese Academy of Sciences for financial support.
REFERENCES
■
(1) (a) Bentley, K. W.The Isoquinoline Alkaloids; CRC Press: Boca
Raton, 1998; ISBN 905702229X, Vol. 1: Chemistry and Biochemistry
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Tetrahydroisoquinoline Antitumor Antibiotics: Scott, J. D.; Williams,
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Isoquinoline Alkaloids: Bentley, K. W. Nat. Prod. Rep. 2006, 23, 444.
(d) Quinoline, Quinazoline and Acridone Alkaloids: Michael, J. P.
Nat. Prod. Rep. 2008, 25, 166.
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The Journal of Organic Chemistry
Note
NOTE ADDED AFTER ASAP PUBLICATION
■
The toc/abstract graphic, Scheme 1, Table 1, and Table 2
contained errors in the version published ASAP March 5, 2012.
The correct version reposted March 23, 2012.
3588
dx.doi.org/10.1021/jo2025114 | J. Org. Chem. 2012, 77, 3583−3588