Synthesis of 2H-chromenes and 1,2-dihydroquinolines from aryl aldehydes, amines, and alkenylboron compounds

Article abstract of DOI:10.1016/j.jorganchem.2008.11.050

The one-step reaction of salicylaldehydes with amines and alkenyl boronic acids or alkenyl trifluoroborates to form 2H-chromenes (2H-1-benzopyrans) has been investigated in more detail and new suitable conditions have been identified, including the use of

Full text of DOI:10.1016/j.jorganchem.2008.11.050

Journal of Organometallic Chemistry 694 (2009) 1747–1753
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Journal of Organometallic Chemistry
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Synthesis of 2H-chromenes and 1,2-dihydroquinolines from aryl aldehydes,
amines, and alkenylboron compounds
*
Nicos A. Petasis , Alexey N. Butkevich
Department of Chemistry and Loker Hydrocarbon Research Institute, University of Southern California, Los Angeles, CA 90089-1661, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The one-step reaction of salicylaldehydes with amines and alkenyl boronic acids or alkenyl trifluorobo-
rates to form 2H-chromenes (2H-1-benzopyrans) has been investigated in more detail and new suitable
conditions have been identified, including the use of tertiary amines and protic solvents including water.
This process was applied to a concise synthesis of a tocopherol analog. The analogous condensation reac-
tion between 2-sulfamidobenzaldehydes and alkenyl trifluoroborates provides an efficient synthesis of
1,2-dihydroquinoline derivatives.
Received 10 November 2008
Accepted 17 November 2008
Available online 30 November 2008
Keywords:
Alkenyl boronic acid
Alkenyl trifluoroborate
Salicylaldehyde
Chromene (benzopyran)
Tocopherol
Ó 2008 Elsevier B.V. All rights reserved.
Dihydroquinoline
Quinoline
1. Introduction
developed, including the synthesis of amino acids [27], amino alco-
hols [28], and various heterocycles [25].
The 2H-chromene (2H-1-benzopyran) moiety is a common
structural feature of numerous biologically active molecules [1,2]
and is widely occurring in the structures of many natural flavo-
noids and anthocyanins [3], as well as the members of the vitamin
E family (tocopherols and tocotrienes) [4–10]. A variety of methods
are known for the synthesis of this class of compounds [2,4–14],
typically starting with 2-hydroxy-acetophenone derivatives or di-
rectly from phenols via cyclization methods, electrophilic aromatic
substitution, or by relying on palladium-catalyzed processes.
The 1,2-dihydroquinoline moiety is another widely occurring
structural fragment in a large number of molecules with a range
of biological properties, and has also been synthesized with a vari-
ety of methods, including additions to activated quinoline deriva-
tives [15–19], and various domino-type condensation processes
[20–23].
Herein, we report our studies on a common methodology for
the synthesis of 2H-chromenes as well as 1,2-dihydroquinoline
derivatives by utilizing aryl aldehydes and organoboron com-
pounds [24]. This approach is based on our one-step three-compo-
nent reaction between an amine, an aldehyde and an organoboron
compound, that we introduced some time ago and which has
evolved into a versatile and synthetically useful process [25,26].
Many variations and applications of this chemistry have been
We have earlier reported that the one-step reaction between sal-
icylaldehydes (1), amines (2), and alkenyl or aryl boronic acids (3),
at room temperature, forms aminophenol derivatives (5) [29].
When alkenyl boronic acids are used, and the reaction is performed
at higher temperature, it leads to the formation of 2H-chromenes
(2H-1-benzopyrans) (6), a process shown by Finn to proceed effi-
ciently under catalytic amounts of the amine component [30]. Sub-
sequent reports by several groups have shown that this chemistry
works well in ionic liquids [31,32], under microwave conditions
[33], and by employing potassium trifluoroborates [34].
The above approach to the synthesis of 2H-chromenes (6) was
postulated to involve an intramolecular nucleophilic displacement
of an ammonium leaving group, as shown in intermediate 7
(Scheme 1), to form directly the product [30]. However, it is also
possible that an alternative fragmentation takes place, as shown
in intermediate 8, to form initially intermediate 9, which can un-
dergo electrocyclic ring closure to form product 6. Based on this
hypothesis we investigated additional aspects of this process,
which are reported herein. We also extended this chemistry to
the synthesis of 1,2-dihydroquinolines, by starting with 2-
sulfamidobenzaldehydes.
2. Results and discussion
The overall unified strategy for the synthesis of both 2H-chrom-
enes (18) and 1,2-dihydroquinolines (19) is shown in Scheme 2.
* Corresponding author. Tel.: +1 213 740 6683.
E-mail address: petasis@usc.edu (N.A. Petasis).
0022-328X/$ - see front matter Ó 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2008.11.050

1748
N.A. Petasis, A.N. Butkevich / Journal of Organometallic Chemistry 694 (2009) 1747–1753
R5
R5
R4
R1
R4
(Scheme 4). Notably, highly sterically hindered secondary amines
(e.g. 2,2,6,6-tetramethylpiperidine) proved less reactive than the
less congested Hünig’s base, which produced the product even
though is considered to be non-nucleophilic. On the other hand,
tetrabutylammonium hydroxide, a relatively strong base, was
found to be completely ineffective.
R5
R4
N
R3
N
N
O
R2
R6
R6
R6
H
R3
2
rt
-H2O
R2
R1
OH
R3
OH
B
B
OH
OH
O
R2
1
HO
OH
4
5
R1
3
Taken together, these findings suggest a possible mechanism
that includes a nucleophilic attack of the amine (15) to the alde-
hyde carbonyl, which can be aided by an intramolecular hydrogen
bond with the phenolic hydroxyl group (20). The resulting inter-
mediate (24) can then react with the boronic acid (21) to generate
an ion pair (25) consisting of an electrophilic ammonium species
and a nucleophilic borate species, analogously to the postulated
mechanism of our three-component process [25]. Subsequent con-
jugate addition of the alkenyl group can lead to an ammonium
phenolate intermediate (26), which subsequently can undergo
fragmentation to form the 2H-chromene (23) directly, or via inter-
mediate 27.
R4
R4
R4
N
R3
R3
R3
X
X
X
N
N
R6
R6
R6
10
R6
heat
or
R2
O
R2
O
R2
O
O
9
R2
X=H or B(OH)2
8
7
6
Scheme 1.
R6
(HO)2B
R4
N
X=O
R3
R5
R4
N
O
O
R2
2.2. Synthesis of an alkyl analog of ( )-
a-tocopherol
R6
R3
R5
R6
R2
13
18
15
R6
or
In order to illustrate the potential utility of this methodology for
the synthesis of chromane derivatives related to Vitamin E, we
have carried out a short synthesis of tocopherol analogs. The com-
monly available synthetic racemic tocopherols are produced on
large industrial scale by Friedel–Crafts alkylation of trimethylhy-
droquinone with the tertiary allyl alcohol isophytol, or the primary
allyl alcohol phytol in the presence of a Brønsted or Lewis acid,
such as ZnCl2 [8]. The synthesis of individual stereoisomers of
tocopherol and its analogs have also been reported. These conver-
gent syntheses rely on palladium couplings or other reactions be-
X
H
X
R2
KF3B
N
R2
SO2R7
19
X=NSO2R7
11, X=O
12, X=NSO2R7 14
16, X=O
R2
17, X=NSO2R7
Scheme 2.
Thus, reaction of salicylaldehydes (11) with alkenyl boronic acids
(13) or alkenyl trifluoroborates (14) in the presence of an amine
(15), leads to the initial formation of an amino phenol intermediate
(16), which upon heating undergoes cyclization to form the 2H-
chromene product (18). A similar sequence starting with the mesyl
derivatives of 2-aminobenzaldehydes (12) and alkenyl trifluorobo-
rates (14) proceeds through intermediate (17) to form 1,2-dihydro-
quinolines (19).
tween the chromane derivative with
component [7,9].
a suitable side chain
The use of our three-component process for tocopherol synthe-
sis offers an alternative approach and allows the introduction of
the side chain in one or two convenient steps (Scheme 5).
Thus, reaction of salicylaldehyde derivative 28 [5] with boronic
acid 29 and dibenzylamine generated the chromene product 30,
that was converted to the tocopherol analog 31, upon catalytic
hydrogenation. The key cyclization step was relatively slow in this
case (probably due to the bulkiness of the aldehyde 28) and it re-
quired prolonged heating and addition of equivalent amount of
the amine, providing 57% yield of the intermediate 30. However,
2.1. Synthesis of 2H-chromenes from salicylaldehydes
The one-step synthesis of 2H-chromenes, outlined in Scheme 1,
has the advantage of being short and efficient, and it allows the di-
rect incorporation of substituents onto the molecule. In order to
further explore the scope of this process, we have carried out a
more detailed investigation, which indicated that the outcome of
this process depends heavily on the reaction conditions.
The secondary amines are generally the most reactive in this
chemistry and several conditions have been reported for this pro-
cess [29–31,34]. We have also found that this transformation
works particularly well in protic solvents, including ethanol and
water. Among the most efficient is the use of dibenzylamine in
water, and under these conditions salicylaldehyde 20 was con-
verted to 2H-chromene 23 quite efficiently, both with alkenyl
boronic acids (e.g. 21) as well as alkenyl trifluoroborates (e.g.
22), as shown in Scheme 3.
amine
(HO)2B
Br
Br
O
+
EtOH or H2O
70 oC
Ph
O
Ph
O H
20
21
23
R4
R3
R5
N
15
R4
R4
Conditions
Yield %
R3
R5
R3
R5
N
N
Et3N (1eq), EtOH, 24h
Et3N (2eq), EtOH, 24h
53
61
Br
Br
OH
Et3N (0.1eq), EtOH, 24h traces
O
O
Ph
Et3N (1eq), H2O, 48h
iPr2EtN (1eq), EtOH, 24h
iPr2EtN (1eq), EtOH, 7d
DABCO (1eq), EtOH, 7d
38
31
37
14
24
Surprisingly, however, we have also found out that tertiary
amines can also mediate this process, but they are less effective
26
21
R4
N
R3
R5
Br
(HO)3B
(HO)2B
EtOH, 24h
N
traces
Ph
N
H
Ph
Br
Br
O
H
Ph
25
O
21
Ph
Ph
PhNMe2, EtOH, 24h
pyridine, EtOH, 24h
Bu4NOH, EtOH, 24h
0
0
0
+
H2O
80 oC, 3h
or
OH
O
Ph
KF3B
Br
27
20
23
82-90%
22
O
Ph
Scheme 3.
Scheme 4.

N.A. Petasis, A.N. Butkevich / Journal of Organometallic Chemistry 694 (2009) 1747–1753
1749
Lewis acid
R3N
B(OH)2
R
O
KF3B
29
BnO
BnO
N
Ph
O
NH
SO2Me
Bn2NH (1 eq)
PhMe
80 oC, 18 h
Ph
SO2Me
OH
O
R
37
BuOH
110 oC, 24 h
22
36
28
R3N Lewis acid
57%
30
R = (CH2)13Me
Conditions
Yield %
80%
TMSCl (1eq), Et3N (2eq), MeCN
TMSCl (2eq), Et3N (excess)
TMSCl (5eq), Et3N (5eq)
TMSCl (2eq), Et3N (2eq)
TMSCl (2eq), iPrEt3N (2eq)
TMSCl (2eq), Et3N (2eq), 4 MS
TMSOTf (2eq), Et3N (2eq)
TBSCl (2eq), Et3N (2eq)
BF3.Et2O (2eq), Et3N (2eq)
BCl3 (2eq), Et3N (2eq)
21
32
H2, 5% Pd/C
EtOH, 60 oC
NR3
OH
F2B
HO
HO
0
59
Ph
O
O
N
31
31
SO2Me
38
27
39
35
48
44
mixture
traces
0
NR3
AlCl3 (2eq), Et3N (2eq)
Y(X)2B
(2R
,4'
R,8'R)-α-Tocopherol
32
ZnBr2 (2eq), Et3N (2eq)
FeCl3 (2eq), Et3N (2eq)
0
Ph
N
Scheme 5.
TiCl4 (2eq), Et3N (2eq)
0
SO2Me
22 X=Y=F
41 X=F, Y=OH
Ti(Oi-Pr)4 (2eq), Et3N (2eq)
0
40
no side reactions were observed and the unreacted aldehyde was
completely recovered. Addition of an acid catalyst (Amberlyst 15
resin) did not accelerate the reaction. At lower temperature
(70 °C in ethanol), the yield dropped down to 20% (with the con-
version remaining nearly quantitative), but at high temperatures
(180 °C) substantial decomposition occurred. Subsequent hydroge-
nation of 30 under mild conditions resulted in simultaneous deb-
enzylation and reduction of the double bond and afforded 31 in
NR3
NR3
NR3
or
Ph
SO2Me
N
Ph
N
N
Ph
N
Ph
SO2Me
44
SO2Me
SO2Me
43
42
Scheme 7.
37
80% yield. Unlike all-rac-a-tocopherol (32), which is a viscous
air-sensitive oil and therefore is commonly used in the protected
form (an acetate or other ester), compound 31 is an air-stable crys-
talline solid.
presence of 2 equiv. of trimethylsilyl chloride and 2 equiv. of
triethylamine.
Following the pioneering work of Vedejs [36] on the synthesis
of potassium organotrifluoroborates (RBF3K) from boronic acids
(RB(OH)2), and their use in combination with trimethylsilyl chlo-
ride to generate in situ organodifluoroboranes (RBF2), the use of
organotrifluoroborates in synthesis have attracted considerable
attention and new applications, recently reviewed by Genet [37],
Stefani [38] and Molander [39]. We have also been investigating
the use of these versatile organoboron compounds in our three-
component reactions, as well as other processes. In fact, the con-
version of styryl trifluoroborate (22) to fluorinated alcohols and
amides using electrophilic fluorinating agents, was one of the ear-
liest synthetic applications of this class of compounds [40].
Herein, we report the use of alkenyl trifluoroborates for the syn-
thesis of 1,2-dihydroquinolines (Scheme 7). For example, under the
optimal conditions, reaction of 2-(methanesulfamido)benzalde-
hyde (36) with styryl trifluoroborate (22) gave the expected prod-
uct (37) in 59% yield.
Upon varying the reaction conditions, it was found that running
the reaction in anhydrous toluene and increasing the amount of
TMSCl to 2 equiv. significantly increased the yield of the product.
Use of only 1 equiv. of Et3N led to the formation of mixtures, while
the increase in concentration of the base did not improve the reac-
tion. The yield of 37 was 32% when the reaction was run in pure
Et3N, while running the reaction in the presence of 5 equiv. TMSCl,
along with 5 equiv. Et3N failed to provide any product. Other nitro-
2.3. Synthesis of 1,2-dihydroquinolines from 2-sulfamido-
benzaldehydes and alkenyl trifluoroborates
Although the three-component reaction among aryl aldehydes,
amines, and organoboron compounds works very well with salicyl-
aldehydes (1) and is quite useful for the synthesis of 2H-chromenes
(Scheme 1), a similar approach to 1,2-dihydroquinolines by using
2-aminobenzaldehydes (33) [35] is not effective [30], while the
limited stability of this type of aldehydes further complicates their
use.
Unlike simple 2-aminobenzaldehydes (33), their N-protected
analogs are quite stable at ambient temperature. Among the vari-
ous possibilities, we chose to investigate the use of the readily
available 2-sulfamidobenzaldehydes (34), whose sulfanilide pro-
ton Ar(RSO2)N–H is very similar in acidity to the phenolic proton
of salicylaldehydes ArO–H. For example, the pKa of 2-(methanesul-
famido)benzaldehyde (36) is calculated to be 8.9, while the the pKa
of salicylaldehyde is 8.2 at 25 °C. In both cases, the acidity is fur-
ther enhanced due to the intramolecular hydrogen bond (Scheme
6).
Indeed, following several exploratory studies, we have found
suitable conditions for the one-step conversion of 2-sulfamidoben-
zaldehydes to 1,2-dihydroquinolines. As shown in Scheme 7, this
process works best with the use of alkenyl trifluoroborates in the
Ph
N
Ph
Ph
R6
R6
Ph
N
Ph
O
KF3B
H
O
O
O
O
+
+
NH
SO2Me
BF3 Et O
2
(2 eq)
N
Ph
SO2Me
37 (30%)
NH2
NH
Ph
NH
O H
N H
PhMe
80 oC, 18 h
O
S
O
SO2Me
45 (26%)
SO2Me
36 pKa = 8.9
33
34
35 pKa = 8.2
R7
35
22
Scheme 6.
Scheme 8.

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N.A. Petasis, A.N. Butkevich / Journal of Organometallic Chemistry 694 (2009) 1747–1753
R6
R6
R6
R6
Me3SiCl (2 eq)
Et3N (2 eq)
Me3SiCl (2 eq)
Et3N (2 eq)
KF3B
KF3B
R1
R2
O
O
+
+
R2
SO2R7
49a-e
NH
SO2R7
46a-e
PhMe
80 oC, 18 h
NH
SO2R7
PhMe
80 oC, 18 h
N
Ph
SO2R7
47a-e
N
Ph
22
46a or 46c
48a-h
Carbonyl compound
O
1,2-Dihydroquinoline product Yield, %
Trifluoroborate salt
Product
Yield, %
BF3K
47a
47b
59
36
46a
NH
Ms
N
Ph
Ph
49a
48
N
Cl
Ms
48a
48b
48c
Ms
Cl
O
46b
BF3K
BF3K
NH
Ns
N
49b
26
N
Ns
MeO
F3C
Ms
Ns = 2-nitrophenylsulfonyl
OMe
CF3
O
47c
47d
47e
59
46
53
46c
Br
NH
Ms
Br
N
Ph
Ph
Ph
49c
49d
33
60
N
Ms
Ms
MeO
MeO
MeO
MeO
O
46d
46e
NH
Ms
N
BF3K
BF3K
Ms
N
O2N
O2N
Ms
48d
48e
O
NH
Ms
N
Ms
49e
49f
32
18
Br
N
Bu
Ms
Scheme 9.
BF3K
Br
N
48f
gen bases (pyridine, DBU, DABCO, i-Pr2EtN, N,N-dimethylaniline)
were also tested, but only i-Pr2EtN yielded 31% of the product.
Among the Lewis acids studied, only the silyl halides, silyl tri-
flates, and boron trifluoride etherate afforded the desired product.
BF3K
Ph
48g
.
As shown in Scheme 8, in the case of BF3 OEt2, the use of a second-
BF3K
Ph
ary amine (e.g. dibenzylamine), along with the expected 1,2-dihy-
droquinoline product (37) the reaction also yielded the product of
the three-component process (45).
Me
48h
The scope of this process was investigated with several 2-sul-
famidobenzaldehyde derivatives (46a–e), providing 40–60% yields
of the expected 1,2-dihydroquinoline products (47a–e), as shown
in Scheme 9.
The use of various alkenyl trifluoroborates was also investigated
(Scheme 10). While 2-arylvinyl (48a–c), 2-alkenylvinyl (48d) and
2-alkylalkenyl (48e) trifluoroborates provided the expected prod-
ucts (49a–e), the simple unsubstituted vinyltrifluoroborate (48f),
under the same reaction conditions, gave only the corresponding
quinoline product (49f) in low yield (18%). The more substituted
alkenyl trifluoroborates (38g–h) under similar conditions did not
form any product at all, presumably for steric reasons.
The 1,2-dihydroquinoline sulfamide products of this process,
can be easily converted into either 2-substituted quinolines or 2-
substituted 1,2,3,4-tetrahydroquinolines. As an example, we have
performed both of these transformations with compound 37,
which afforded both products (50 and 51) in quantitative yields,
upon basic treatment or catalytic hydrogenation (Scheme 11).
These additional transformations make this chemistry into a con-
venient method for the synthesis of these and other heterocycles.
Scheme 10.
H2 , 5% Pd/C
EtOH, RT, 12h
NaOH, EtOH
50 oC, 12 h
N
Ph
N
Ph
>99%
>99%
N
Ph
SO2Me
SO2Me
50
37
51
Scheme 11.
viously described methods [41,42]. Potassium alkenyltrifluorobo-
rates were prepared according to standard procedures [36,38,39]
from the corresponding alkynes or alkenylboronic acids. Anhy-
drous solvents (acetonitrile and toluene, DriSolvÒ) were purchased
from EMD Chemicals and used directly as supplied.
1H (400 MHz), 13C (100 MHz) and 19F (376 MHz) NMR spectra
were recorded in CDCl3 on a Varian Mercury-400 Spectrometer,
and conformed to the literature data for known compounds. The
purity of the products and the progress of the reactions were mon-
itored by thin layer chromatography on Silica Gel 60 F254 glass
plates (EMD) followed by visualization with potassium permanga-
nate or vanillin stain.
3. Experimental
3.1. Materials and physical measurements
3.2. Synthesis of 6-bromo-2-phenyl-2H-chromene (23)
All reactions were performed in sealed vials with magnetic stir-
ring, under an atmosphere of dry nitrogen. All chemicals were pur-
chased commercially from Sigma–Aldrich (unless noted
otherwise). 2-Sulfamidoaldehydes were prepared according to pre-
The mixture of either 2-phenylvinylboronic acid (148 mg,
1.0 mmol) or potassium 2-phenylvinyltrifluoroborate (210 mg,
1.0 mmol), with 5-bromosalicylaldehyde (201 mg, 1.0 mmol) and

N.A. Petasis, A.N. Butkevich / Journal of Organometallic Chemistry 694 (2009) 1747–1753
1751
dibenzylamine (197 mg, 1.0 mmol) in 2 mL of water was stirred at
80 °C for 3 h. The reaction mixture was extracted with 3 Â 10 mL
CH2Cl2, dried over Na2SO4, filtered and evaporated. The yellow syr-
upy residue was purified by column chromatography (SiO2,
CH2Cl2–hexane 1:5). The product, 6-bromo-2-phenyl-2H-chro-
mene (23) (Rf ꢀ 0.4) was eluted, then the mixture was left on sol-
vent-wet silica until the purple-colored band faded completely,
and more product was eluted with CH2Cl2. Total yield 235 mg
(82%), viscous yellowish oil.
(31) as white crystals. The compound can be recrystallized from
methanol. 1H NMR (400 MHz, CDCl3): d 0.90 (t, J = 6.8 Hz, 3H),
1.18–1.80 (m, 27H), 1.94–2.03 (m, 1H), 2.11 (s, 3H), 2.14 (s, 3H),
2.17 (s, 3H), 2.61–2.73 (m, 2H), 3.78–3.88 (m, 1H), 4.25 (s, 1H).
13C NMR (100 MHz, CDCl3): d 11.2, 11.7, 12.1, 14.1, 22.7, 23.2,
25.6, 28.0, 29.4, 29.6, 29.66, 29.69, 31.9, 35.4, 74.8, 118.3, 118.7,
120.8, 122.3, 144.8, 147.0.
3.6. General procedure for the synthesis of 1,2-dihydroquinolines
(47a–e, 49a–e) and quinolines (49f)
3.3. General procedure for the synthesis of 6-bromo-2-phenyl-2H-
chromene (23)
The mixture of solid alkenyl trifluoroborate (1 mmol), the corre-
sponding carbonyl compound (1 mmol) and a stirring bar were
sealed in a 10 mL glass vial, which was subsequently flushed with
dry nitrogen. 2.5 mL of anhydrous solvent (acetonitrile or toluene)
was injected followed by 0.28 mL (203 mg, 2 mmol) of triethyl-
amine, and the resulting suspension was stirred at room tempera-
ture for 5 min. Chlorotrimethylsilane (TMSCl; 0.26 mL, 223 mg,
2.05 mmol) was then added in one portion. The mixture was stir-
red at 80 °C for 18 h, cooled and diluted with 30 mL of ethyl acetate
and 20 mL of water. The layers were separated and the aqueous
layer was extracted with 3 Â 20 mL of ethyl acetate. The combined
organic layers were dried over Na2SO4, filtered and evaporated. The
products were isolated by column chromatography on silica (elu-
ent – ethyl acetate-hexane) and crystallized upon trituration with
diethyl ether–pentane.
The solution of 5-bromosalicylaldehyde (201 mg, 1 mmol), 2-
phenylvinylboronic acid (148 mg, 1 mmol) and the appropriate
amount of a secondary or tertiary amine in 2.5 mL of absolute eth-
anol was prepared in a 2 dram screw-cap glass vial, flushed with
dry nitrogen, and stirred at 70 °C for the indicated amount of time.
The reaction mixture was then evaporated to dryness and pure 6-
bromo-2-phenyl-2H-chromene (23) was isolated by column chro-
matography on silica (eluent, dichloromethane:hexane 1:2) as
light yellow oil. 1H NMR (400 MHz, CDCl3): d 5.93 (dd, J = 9.9 Hz,
3.4 Hz, 1H), 6.00–6.04 (m, 1H), 6.55 (dd, J = 9.9 Hz, 1.1 Hz, 1H),
6.79 (d, J = 8.6 Hz, 1H), 7.24 (d, J = 2.3 Hz, 1H), 7.30 (dd, J = 8.6 Hz,
2.3 Hz, 1H), 7.42–7.58 (m, 5H). 13C NMR (100 MHz, CDCl3): d
77.2, 113.0, 117.7, 122.9, 123.1, 125.9, 127.0, 128.5, 128.7, 129.0,
131.9, 140.1, 152.1.
3.6.1. 1-(Methylsulfonyl)-2-phenyl-1,2-dihydroquinoline (47a)
1H NMR (400 MHz, CDCl3): d 2.79 (s, 3H), 6.04 (d, J = 5.8 Hz, 1H),
6.34 (dd, J = 9.6 Hz, 5.8 Hz, 1H), 6.86 (d, J = 9.6 Hz, 1H), 6.21–6.31
(m, 6H), 7.36–7.40 (m, 1H), 7.56–7.60 (m, 1H). 13C NMR
(100 MHz, CDCl3): d 37.7, 56.9, 126.3, 126.5, 126.7, 126.9, 127.20,
127.24, 127.97, 127.99, 128.4, 128.6, 132.9, 138.1.
3.4. Synthesis of 6-(benzyloxy)-5,7,8-trimethyl-2-tetradecyl 2H-
chromene (30)
3-(Benzyloxy)-6-hydroxy-2,4,5-trimethylbenzaldehyde (28) was
prepared from trimethylhydroquinone according to the procedure
reported for the 3-methoxy analog [5]. 1-Hexadecenylboronic acid
was prepared in 69% yield from 1-hexadecyne (technical grade,
90%, Alfa Aesar) and catecholborane [43]. The suspension of 28
(135 mg, 0.5 mmol), 1-hexadecenylboronic acid (134 mg,
0.5 mmol) and dibenzylamine (100 mg, ꢀ0.5 mmol) in 1 ml of 1-
butanol was prepared in a 1 dram screw-cap glass vial, flushed
with dry nitrogen, and stirred at 110 °C for 24 h. The reaction mix-
ture was evaporated to dryness. The product was isolated by col-
umn chromatography on silica (eluent – ethyl acetate:hexane
1:100), followed by unreacted 28 (eluent – ethyl acetate:hexane
1:9). The fractions containing the product were evaporated to
dryness, and the solid residue was recrystallized from ethanol,
yielding 135 mg (57%) of crystalline air-sensitive 6-(benzyloxy)-
3.6.2. 1-[(2-Nitrophenyl)sulfonyl]-2-phenyl-1,2-dihydro-quinoline
(47b)
1H NMR (400 MHz, CDCl3): d 6.14 (d, J = 6.0 Hz, 1H), 6.21 (dd,
J = 9.6 Hz, 6.0 Hz, 1H), 6.41 (d, J = 9.6 Hz, 1H), 7.09 (dd, J = 7.1 Hz,
1.7 Hz, 1H), 7.19–7.31 (m, 6H), 7.33-7.41 (m, 3H), 7.51 (d,
J = 7.9 Hz, 1H), 7.63 (t, J = 7.9 Hz, 1H), 7.68 (d, J = 7.9 Hz, 1H). 13C
NMR (100 MHz, CDCl3): 57.1, 123.5, 124.9, 126.4, 127.1, 127.3,
127.5, 128.0, 128.1, 128.4, 128.5, 129.0, 130.4, 130.6, 130.8,
131.8, 133.7, 137.4, 147.7.
3.6.3. 7-Bromo-1-(methylsulfonyl)-2-phenyl-1,2-dihydro-quinoline
(47c)
5,7,8-trimethyl-2-tetradecyl-2H-chromene
(30).
1H
NMR
1H NMR (400 MHz, CDCl3): d 2.82 (s, 3H), 6.03 (d, J = 5.8 Hz, 1H),
6.36 (ddd, J = 9.6 Hz, 5.8 Hz, 1.2 Hz, 1H), 6.62 (d, J = 9.6 Hz, 1H),
7.10 (dd, J = 8.1 Hz, 1.2 Hz, 1H), 7.25–7.37 (m, 6H), 7.75 (s, 1H).
13C NMR (100 MHz, CDCl3): d 38.2, 56.9, 121.7, 125.5, 126.8,
127.2, 127.6, 127.8, 128.2, 128.6, 129.5, 129.6, 134.1, 137.7.
(400 MHz, CDCl3): d 0.92 (t, J = 6.8 Hz, 3H), 1.10–1.42 (m, 22H),
1.43–1.70 (m, 3H), 1.77–1.90 (m, 1H), 2.16 (s, 3H), 2.25 (s, 3H),
2.27 (s, 3H), 4.69–4.77 (m, 3H), 5.77 (dd, J = 10.0 Hz, 3.3 Hz, 1H),
6.60 (dd, J = 10.0 Hz, 1.7 Hz, 1H), 7.34–7.39 (m, 1H), 7.;7.46 (m,
2H), 7.49–7.54 (m, 2H). 13C NMR (100 MHz, CDCl3): d 11.5, 11.7,
13.1, 14.1, 22.7, 25.3, 29.4, 29.61, 29.67, 29.7, 31.9, 34.8, 74.1,
74.6, 119.0, 121.7, 122.6, 123.6, 125.4, 127.7, 127.8, 128.5, 130.4,
137.8, 147.6, 149.1.
3.6.4. 6,7-Dimethoxy-1-(methylsulfonyl)-2-phenyl-1,2-
dihydroquinoline (47d)
1H NMR (400 MHz, CDCl3): d 2.71 (s, 3H), 3.78 (s, 3H), 3.82 (s,
3H), 5.89 (d, J = 5.8 Hz, 1H), 6.14 (dd, J = 9.6 Hz, 5.8 Hz, 1H), 6.65
(s, 1H), 6.71 (d, J = 9.6 Hz, 1H), 7.06 (s, 1H), 7.14–7.23 (m, 3H),
7.28–7.33 (m, 2H). 13C NMR (100 MHz, CDCl3): d 37.0, 55.8, 56.5,
108.7, 110.9, 121.0, 124.4, 125.87, 125.90, 127.1, 127.8, 128.2,
138.1, 147.4, 148.5.
3.5. Synthesis of 5,7,8-trimethyl-2-tetradecylchroman-6-ol (31)
Compound 30 (96 mg, 0.2 mmol) was suspended in 10 mL of
anhydrous ethanol in a 25 mL round-bottom flask. 10 mg of 5% pal-
ladium on carbon was added under nitrogen. The reaction mixture
was stirred overnight at 60 °C under hydrogen (1 atm). Upon cool-
ing, the product precipitated. The reaction mixture was filtered
through a short plug of Celite, washed with dichloromethane
(100 mL). The filtrate was evaporated and dried in vacuo to give
62 mg (80%) of pure 5,7,8-trimethyl-2-tetradecylchroman-6-ol
3.6.5. 1-(Methylsulfonyl)-6-nitro-2-phenyl-1,2-dihydro-quinoline
(47e)
1H NMR (400 MHz, CDCl3): d 2.87 (s, 3H), 6.12 (d, J = 6.0 Hz, 1H),
6.46 (dd, J = 9.6 Hz, 6.0 Hz, 1H), 6.90 (d, J = 9.6 Hz, 1H), 7.24–7.35
(m, 5H), 7.71 (d, J = 9.1 Hz, 1H), 8.06 (dd, J = 9.1 Hz, 2.5 Hz, 1H),

1752
N.A. Petasis, A.N. Butkevich / Journal of Organometallic Chemistry 694 (2009) 1747–1753
8.10 (d, J = 2.5 Hz, 1H). 13C NMR (100 MHz, CDCl3): d 39.2, 57.4,
121.8, 123.4, 124.6, 125.6, 127.0, 128.0, 128.5, 128.7, 129.7,
137.4, 138.9, 145.0.
up as described above in the general procedure. Rf values (ethyl
acetate:hexane 1:3): for compound 37 Rf = 0.4, for compound 45
Rf = 0.6; both stained grey upon heating with vanillin stain. The
products were isolated by column chromatography on silica (elu-
ent – ethyl acetate:hexane 1:9, changed to 1:5 after elution of
the compound 45), yielding 124 mg (26%) of 45 and 86 mg (30%)
of 37.
3.6.6. 2-(4-Chlorophenyl)-1-(methylsulfonyl)-1,2-dihydro-quinoline
(49a)
1H NMR (400 MHz, CDCl3): d 2.79 (s, 3H), 5.99 (d, J = 6.0 Hz, 1H),
6.31 (dd, J = 9.8 Hz, 6.0 Hz, 1H), 6.87 (d, J = 9.8 Hz, 1H), 7.21–7.33
(m, 7H), 7.54–7.59 (m, 1H). 13C NMR (100 MHz, CDCl3): d 37.8,
56.2, 126.6, 126.75, 126.79, 127.0, 127.9, 128.6, 128.7, 128.9,
132.6, 133.9, 136.6.
3.8. Synthesis of 2-phenylquinoline (50)
The solution of 285 mg (1 mmol) of compound 37 and 400 mg
(10 mmol) of NaOH in 10 mL of absolute ethanol was stirred at
50 °C for 12 h. The reaction mixture was then poured into 30 mL
of water, extracted with 3 Â 20 mL of ethyl acetate, and the com-
bined organic extracts were washed with 25 mL of water. The or-
ganic layer was dried over Na2SO4, filtered and evaporated to
give yellowish crystals of 2-phenylquinoline (50) (205 mg, >99%).
1H NMR (400 MHz, CDCl3): d 7.45–7.50 (m, 1H), 7.51–7.57 (m,
3H), 7.71–7.77 (m, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.88 (d, J = 8.3 Hz,
1H), 8.15–8.24 (m, 4H). 13C NMR (100 MHz, CDCl3): d 119.0,
126.2, 127.1, 127.4, 127.5, 128.8, 129.3, 129.6, 129.7, 136.7,
139.7, 148.3, 157.3.
3.6.7. 2-(4-Methoxyphenyl)-1-(methylsulfonyl)-1,2-dihydro-quinoline
(49b)
1H NMR (400 MHz, CDCl3): d 2.78 (s, 3H), 3.77 (s, 3H), 5.98 (d,
J = 5.8 Hz, 1H), 6.29 (dd, J = 9.6 Hz, 5.8 Hz, 1H), 6.80 (d, J = 8.7 Hz,
2H), 6.84 (d, J = 9.6 Hz, 1H), 7.20–7.30 (m, 5H), 7.52–7.56 (m,
1H). 13C NMR (100 MHz, CDCl3): d 37.8, 55.2, 56.6, 113.8, 126.1,
126.5, 126.6, 127.0, 127.5, 128.1, 128.6, 128.7, 129.9, 132.9, 159.4.
3.6.8. 1-(Methylsulfonyl)-2-[4-(trifluoromethyl)phenyl]-1,2-
dihydroquinoline (49c)
1H NMR (400 MHz, CDCl3): d 2.81 (s, 3H), 6.08 (d, J = 6.0 Hz, 1H),
6.37 (dd, J = 9.6 Hz, 6.0 Hz, 1H), 6.90 (d, J = 9.6 Hz, 1H), 7.22–7.31
(m, 3H), 7.48–7.57 (m, 4H), 7.61 (d, J = 7.5 Hz, 1H). 13C NMR
3.9. 1-(Methylsulfonyl)-2-phenyl-1,2,3,4-tetrahydroquino-line (51)
1
(100 MHz, CDCl3): d 37.8, 56.3, 121.2 (q, JC,F = 271 Hz), 125.4 (q,
To the solution of 285 mg (1 mmol) of compound 37 in 10 mL of
absolute ethanol 20 mg of 5% palladium on carbon was added un-
der nitrogen. The reaction mixture was stirred overnight at room
temperature under hydrogen (1 atm), filtered through a short plug
of silica gel and washed with 200 mL of ethyl acetate. The filtrate
was evaporated and dried in vacuo to yield 1-(methylsulfonyl)-2-
phenyl-1,2,3,4-tetrahydroquinoline (51) (290 mg, >99%) as viscous
colorless oil. 1H NMR (400 MHz, CDCl3): d 2.05–2.15 (m, 1H), 2.48–
2.57 (m, 1H), 2.64–2.81 (m, 2H), 2.89 (s, 3H), 5.61 (t, J = 6.8 Hz, 1H),
7.12–7.20 (m, 2H), 7.23–7.37 (m, 6H), 7.82 (d, J = 7.9 Hz, 1H). 13C
NMR (100 MHz, CDCl3): d 25.1, 31.4, 39.0, 59.0, 123.4, 124.5,
125.9, 126.9, 127.0, 128.4, 128.6, 131.4, 136.2, 141.7.
3JC,F = 4 Hz), 126.2, 126.88, 126.91, 126.98, 127.1, 127.6, 127.8,
2
129.0, 130.1 (q, JC,F = 32 Hz), 132.6, 142.3. 19F NMR (376 MHz,
CDCl3): d À62.59.
3.6.9. 2-Cyclohex-1-en-1-yl-1-(methylsulfonyl)-1,2-dihydro-quinoline
(49d)
1H NMR (400 MHz, CDCl3): d 1.35–1.62 (m, 4H), 1.74–1.95 (m,
3H), 2.09–2.20 (m, 1H), 5.15 (d, J = 5.6 Hz, 1H), 5.53–5.58 (m,
1H), 6.00 (dd, J = 9.5 Hz, 5.6 Hz, 1H), 6.64 (d, J = 9.5 Hz, 1H), 7.09–
7.23 (m, 3H), 7.53 (d, J = 7.9 Hz, 1H). 13C NMR (100 MHz, CDCl3):
d 21.9, 22.4, 24.9, 25.1, 37.3, 59.0, 125.4, 125.7, 126.2, 126.4,
126.7, 127.1, 128.1, 128.2, 133.2, 133.8.
Acknowledgements
3.6.10. 7-bromo-2-butyl-1-(methylsulfonyl)-1,2-dihydro-quinoline
(49e)
Financial support by the National Institutes of Health and the
Loker Hydrocarbon Research Institute of the University of Southern
California is gratefully acknowledged.
1H NMR (400 MHz, CDCl3): d 0.84 (t, J = 7.0 Hz, 1H), 1.17–1.47
(m, 6H), 2.66 (s, 3H), 4.65–4.73 (m, 1H), 6.11 (dd, J = 9.6 Hz,
5.8 Hz, 1H), 6.49 (d, J = 9.6 Hz, 1H), 7.01 (d, J = 8.3 Hz, 1H), 7.33
(dd, J = 8.3 Hz, 1.7 Hz, 1H), 7.77 (d, J = 1.7 Hz, 1H). 13C NMR
(100 MHz, CDCl3): d 13.9, 22.0, 27.2, 32.7, 37.8, 55.1, 121.2,
124.0, 127.0, 127.6, 129.7, 130.1, 130.2, 133.9.
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