BPO-promoted direct oxidative C-H functionalization of unactivated alkanes into 6-alkyl-6H-benzo [c] chromenes under transition-metal-free conditions

Article abstract of DOI:10.1039/c9ob01396b

A simple and efficient BPO-promoted free radical-based cascade reaction of biaryl vinyl ethers with easily available unactivated alkanes has been developed. A series of 6-alkyl-6H-benzo[c]chromenes have been successfully obtained in moderate to high yield

Full text of DOI:10.1039/c9ob01396b

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: L. Ji, Q. Deng, P.
Liu and P. Sun, Org. Biomol. Chem., 2019, DOI: 10.1039/C9OB01396B.
Volume 15
Number 47
21 December 2017
Pages 9945-10124
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Organic &
Biomolecular
Chemistry
Accepted Manuscripts are published online shortly after acceptance,
rsc.li/obc
before technical editing, formatting and proof reading. Using this free
service, authors can make their results available to the community, in
citable form, before we publish the edited article. We will replace this
Accepted Manuscript with the edited and formatted Advance Article as
soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes to the
text and/or graphics, which may alter content. The journal’s standard
Terms & Conditions and the Ethical guidelines still apply. In no event
ISSN 1477-0520
PAPER
I . J. Dmochowski et al.
Oligonucleotide modifi cations enhance probe stability for
shall the Royal Society of Chemistry be held responsible for any errors
single cell transcriptome in vivo analysis (TIVA)
or omissions in this Accepted Manuscript or any consequences arising
from the use of any information it contains.
rsc.li/obc

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 1 of 8
View Article Online
DOI: 10.1039/C9OB01396B
ARTICLE
BPO promoted direct oxidative C–H functionalization of
unactivated alkanes into 6-alkyl 6H-benzo[c]chromenes under
transition-metal-free conditions†
Received 00th June 2019,
Accepted 00th January 2019
Lei Ji,‡ Qinfei Deng,‡ Ping Liu* and Peipei Sun*
DOI: 10.1039/x0xx00000x
A simple and efficient BPO-promoted free radical-based cascade reaction of biaryl vinyl ethers with easily available
unactivated alkanes has been developed. A series of 6-alkyl 6H-benzo[c]chromenes have been successfully obtained in
moderate to high yields under transition-metal-free conditions. This method can also be utilized to synthesize 6-alkyl 6H-
benzo[c]thiochromenes
from
the
corresponding
biaryl
vinyl
thioethers.
polymer, stemmed from the polymerization of 6-alkyl substituted
6H-benzo[c]chromene with dithienyl benzothiadiazole or
diketopyrrolopyrrole, can also be applied to solar cells.10 Thus, the
rapid and efficient construction of alkyl-substituted 6H-
benzo[c]chromene derivatives is of great significance in the fields of
medicinal chemistry and materials.
Introduction
The development of effective methods for C–H bond activation and
functionalization is particularly important in organic synthesis.1
Compared with the traditional organic reactions, the direct C–H
functionalization can achieve the transformation of simple
hydrocarbons to complex organic molecules and reduce the waste
emission.2 Relative to the C(sp2)–H or C(sp)–H bond, the direct
C(sp3)–H bond functionalization of alkenes is inherently difficult,
probably due to its much higher bond dissociation energies.3
Transition-metal catalyzed C(sp3)–H bond activation and
functionalization to construct carbon–carbon bonds and carbon–
heteroatom bonds has aroused much attention in past decade.4
Despite this, most of the transition-metal catalysts are expensive
and toxic, and are difficult to completely remove from the
products.5 Sometimes, in order to enhance catalytic activity, using
expensive supporting ligands is unavoidable. Therefore, it is
necessary to develop efficient methods for the direct
functionalization of C(sp3)–H bond under transition-metal-free
conditions.6
Benzo[c]chromene is a fundamental building block of some
drugs and biologically active natural products (Fig. 1).7 For example,
Cannabinol, an important type of cannabinoids, has antimicrobial
activity and sedative effects.8 Pulchrol (III) and pulchral (IV),
isolated from the metabolites of plant Bourreria pulchra, show
antiviral and antipyretic activities.9 The common feature of the
above three drug molecules is that there are two methyl groups
linked to the C6-position of 6H-benzo[c]chromene. In addition, the
OH
CHO
OH
OMe
OMe
O
O
Pulchrol
O
Pulchral
Cannabinol
Fig.
1
Examples of bioactive compounds based on
benzo[c]chromene skeleton.
Many efforts have been devoted to the construction of 6H-
benzo[c]chromene via C–H functionalization strategy. In 2004,
Fagnou et al. developed a palladium-catalyzed intramolecular C–H
arylation of ortho-Bromo-substituted aryl benzyl ethers to
synthesize benzo[c]chromenes (Scheme 1a).11a The same group
subsequently extended the substrates to aryl chlorides and iodine
compounds.11b-c Following a similar inspiration, McGlacken et al.
described the C–H arylation with PdO impregnated Fe3O4 catalyst in
the absence of ligands.11d In 2011, Lei and co-workers reported Co-
catalyzed intermolecular coupling of non-activated arenes with aryl
halides, and found that intramolecular C–H arylation could also
proceed smoothly to obtain 6H-benzo[c]chromene.12 Interestingly,
Shi et al. demonstrated an entirely different intramolecular radical
substitution of ortho-halogen-substituted aryl benzyl ethers in the
presence of tBuOK and neocuproine to construct 6H-
benzo[c]chromenes.13 An alternative method involved the
intramolecular C–H arylation was described by Du et al., who
employed phenyl diazonium tetrafluoroborate with Pd(OAc)2
(Scheme 1b).14 Besides the direct C–H arylation, Pd-catalyzed
intramolecular decarboxylative coupling of aryl carboxylic acids with
aryl bromides,15 Pd-catalyzed and/or KOtBu mediated
intramolecular O-arylation of 2’-bromobiphenyl-2-methanol via
†In memory of professor Yongmin Zhang
School of Chemistry and Materials Science, Nanjing Normal University; Jiangsu
Provincial Key Laboratory of Material Cycle Processes and Pollution Control;
Jiangsu Collaborative Innovation Center of Biomedical Functional Materials,
Nanjing 210023, China. E-mail: pingliu@njnu.edu.cn; sunpeipei@njnu.edu.cn
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See DOI:
10.1039/x0xx00000x
‡These authors contributed equally to this work.
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 2 of 8
ARTICLE
Journal Name
SNAr pathway,16 were also successfully applied to the synthesis of hydroperoxide (TBHP), dicumyl peroxide (DCP), di-lauroyl peroxide
View Article Online
DOI: 10.1039/C9OB01396B
6H-benzo[c]chromene derivatives. Recently, we used biaryl vinyl (LPO), benzoyl peroxide (BPO), (NH4)S2O8, K2S2O8 or Na2S2O8 were
ethers as the precursor to obtain 6-fluoroalkyl 6H- tested (entries 3−10), in which BPO was proved to be most effective
benzo[c]chromenes
via
a
visible-light-promoted
radical and the reaction gave the product 3aa in 65% yield (entry 7).
Adjustment of the amount of BPO to 4 equiv. or 2 equiv. did not
effectively increase the yield of 3aa (entries 11 and 12). Prolonging
the reaction time to 24 h, the yield of 3aa increased to 70% (entry
13). Additionally, inferior results were obtained at lower or higher
temperature than 100 °C (entries 14−16). It should be noted that
the reaction did not occur under air atmosphere (entry 17).
Furthermore, The presence of transition-metal compounds (10
mol%) such as CuBr or FeCl2 could not improve the yield (entries 18
and 19). Finally, equivalent (3 or 5 equiv.) amount of cyclohexane in
solvent 1,2-dichloroethane (DCE) resulted in lower yields of 3aa
(entry 20).
addition/cyclization reaction.17
Previous works
a) Intramolecular C(sp2)-H arylation with aryl halide
2004, Fagnou et al.
2016, McGlacken et al.
[Pd], P ligand, base
H
or [Co], LiHMDS
O
O
X
2011, Lei et al.
O
tBuOK, neocuproine
X = Cl, Br, I
2011, Shi et al.
Table 1 Optimization of reaction conditionsa
b) Pd-Catalyzed intramolecular decarboxylative coupling
of aryl carboxylic acid with aryl bromide
-
N2+BF4
2012, Du et al.
Oxidant, Additive
+
H
Pd(OAc)2, CH3CN
temperature
O
O
3aa
K2CO3, reflux
O
1a
O
2a
Entry Additive Oxidant
(equiv.)
Temp.
(oC)
Tim
e
Yield
(%)b
This work
c) BPO promoted direct oxidative C(sp3)-H Functionalization cascade cyclization
R2
R2
(h)
1
2
3
4
5
6
7
8
−
−
−
−
−
−
−
−
−
100
100
100
100
100
100
100
100
12
0
15
<10
<10
15
40
65
0
BPO, 100 o
24 h, Ar
C
TBPB (3)
DTBP (3)
TBHP (3)
DCP (3)
LPO (3)
BPO (3)
(NH4)S2O8
(3)
12
12
12
12
12
12
12
R1
H
+
R1
X
X
X = O, S
Transition-metal-free conditions
Strong base free conditions
Simple operation
Scheme
1
C-H functionalization strategy to access
benzo[c]chromene derivatives.
The above methods are efficient for the preparation of 6H-
benzo[c]chromenes. However, some drawbacks such as the use of
transition-metal and/or strong base still exist. In the previous
9
−
K2S2O8 (3)
Na2S2O8 (3)
BPO (4)
BPO (2)
BPO (3)
BPO (3)
BPO (3)
BPO (3)
BPO (3)
BPO (3)
BPO (3)
BPO (3)
100
100
100
100
100
90
12
12
12
12
24
24
24
24
24
24
24
24
0
0
10
11
12
13
14
15
16
17c
18
19
20
−
works, we described
a tunable decarboxylative alkylation of
−
66
55
70
53
68
65
trace
55
25
cinnamic acids in which the unactivated alkanes were used as the
alkyl sources in the presence of organic peroxides.18 To extend the
application of this radical reaction strategy in the synthesis of
heterocyclic derivatives, herein we describe a preparation of 6-alkyl
6H-benzo[c]chromenes through the radical addition/cyclization of
biaryl vinyl ethers under transition-metal-free conditions (Scheme
1c).
−
−
−
−
−
110
120
100
100
100
100
−
CuBrd
Results and discussion
d
FeCl2
The 2-(vinyloxy)-1,1'-biphenyl (1a) was chosen as the model
substrate to test the feasibility. Cyclohexane was used as the alkyl
source and solvent (Table 1). Without the oxidant, the reaction
could not take place at all (entry 1). Using tert-butyl benzoate
(TBPB, 3 equiv.) as the oxidant, at 100 °C and in Ar atmosphere, the
reaction provided the desired product 6-(cyclohexylmethyl)-6H-
benzo[c]chromene (3aa) in 15% yield after 12 h (entry 2). The
oxidants seemed affect the reaction obviously. The organic or
inorganic oxidants, such as di-tert-butyl peroxide (DTBP), tert-butyl
−
12e, 20 f
a
Reaction conditions: 1a (0.2 mmol), oxidant (3 equiv.) and
solvent (2 mL) were carried out in a sealed tube under Ar
atmosphere at 100 oC for 12 h. b Isolated yield, based on 1a. c
d
e
f
Under air. 10 mol%. 2a (3 equiv.) in DCE (2 mL). 2a (5
equiv.) in DCE (2 mL).
With the optimized conditions in hand, we investigated a wide
range of diaryl vinyl ethers (1) with cyclohexane (2a) (Scheme 2).
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 8
Organic & Biomolecular Chemistry
Please do not adjust margins
Journal Name
ARTICLE
When the substrates 1 bearing an electron-donating group (Me, cyclohexane. Reaction conditions: 1a (0.2 mmol), BPOV(i3eweAqrtuicilve.O) nalninde
tBu, MeO) at ortho-, meta- or para- position of the benzene ring A, cyclohexane (2 mL) were carried out in a sealed tube under Ar
DOI: 10.1039/C9OB01396B
the desired products 3ab−3ae were obtained in 70% to 85% yield. atmosphere at 100 oC for 24 h. a Isolated yield, based on 1.
Halogen atom on the para-position of the benzene ring A, such as F,
Cl or Br, provided the addition/cyclization products 3af−3ah in
satisfactory yields (60%−68%). However, strong electron-
withdrawing substituents (CF3, CF3O, CN or acetyl group) exhibited
Subsequently, we explored the substrate scope of unactivated
alkanes (Scheme 3). When cyclopentane and cyclooctane were used
as the alkyl sources at the same reaction conditions, the C(sp3)–H
bond functionalization cascade cyclization proceeded smoothly and
lower reactivity at the same position and produced 3ai−3al in
produced a series of alkylated 6H-benzo[c]chromenes. For several
moderate yields (43%−55%). To our delight, even readily oxidized
substrates 1, the reaction gave the similar results compared with
formyl group was tolerated, providing the cyclization product 3am
the reaction of cyclohexane (3ba–3cc). Linear saturated alkanes
such as pentane and hexane worked well with diaryl vinyl ether 1a,
and the cyclic products 3da, 3ea were formed in 66% and 60% yield,
respectively. But the inseparable isomers were obtained. From
in 40% yield without formation of the aryl acid. Furthermore, when
a methyl was linked to the benzene ring B, the reaction proceeded
smoothly and afforded 3an in 73% yield. This strategy is also
suitable for thioether. When vinyl thioethers were treated with
toluene, however, the oxidation product benzaldehyde was
cyclohexane under the same reaction conditions, the corresponding
detected instead of the addition/cyclization product.
6H-benzo[c]thiochromene derivatives 4a and 4b were obtained in
R2
R2
60% and 45% yield, respectively. If a substrate with internal alkenyl,
e.g., 2-(prop-1-en-1-yloxy)-1,1'-biphenyl was used, however, no
desired product was obtained.
A
A
BPO, 100 o
24 h, Ar
C
+
O
O
R2
R2
1
3
2
A
A
Cl
BPO, 100 o
24 h, Ar
C
R1
R1
+
B
B
X
X
3
X = O, S
1
2a
O
O
O
a
3bb
, 70%
3ba
3bc
, 73%
,68%
Cl
O
O
O
a
O
O
3aa
3ab
, 70%
, 75%
OCH3
3ac
O
, 73%
3cc
,53%
3ca
3cb, 57%
, 62%
F
1
1
2
2
3
3
O
O
O
O
O
3ea
, complex mixture, 60%
3da
, complex mixture, 66%
3af
, 60%
CF3
3ad
, 70%
Cl
3ae
, 85%
Br
Scheme 3 Addition/cyclization of biaryl vinyl ethers with other
alkanes. Reaction conditions: 1 (0.2 mmol), BPO (3 equiv.) and
alkanes (2 mL) were carried out in a sealed tube under Ar
atmosphere at 100 oC for 24 h. a Isolated yield, based on 1.
O
O
O
3ag
, 65%
OCF3
3ai
, 50%
3ah
, 68%
The scalability of this synthetic method was evaluated by
performing the reaction with 5.45 mmol of diaryl vinyl ether 1a
under the optimal conditions. Extending the reaction time to 36 h,
the desire product 3aa was obtained in 61% yield (3.32 mmol, 0.93
g) (Scheme 4, eq (1)). In order to elucidate the mechanism of this
reaction, two control experiments were designed and carried out.
The intramolecular cyclization of 1a did not occur without 2a under
the standard reaction conditions (Scheme 4, eq (2)). Meanwhile,
the template reaction was completely inhibited and the adduct 6
was detected by GC-MS when the radical trapping agent 2,2,6,6-
tetramethyl-1-piperidinyloxy (TEMPO, 2 equiv.) was added. The
product 3aa was not detected and the substrate 1a was almost
quantitatively recovered (Scheme 4, eq (3)). Thus, the reaction
might involve a radical addition to the carbon-carbon double bond
of 1a prior to the cyclization to construct 6H-benzo[c]chromene
skeleton.
O
CN
O
O
O
3aj
, 55%
CHO
3ak
, 45%
3al
, 43%
O
S
O
4a
, 60%
3an
, 73%
3am
, 40%
O
S
4b
, 45%
Scheme
2 Addition/cyclization of biaryl vinyl ethers with
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 4 of 8
ARTICLE
Journal Name
mass spectra were obtained with an AB Triple 5600 mass
View Article Online
spectrometer by ESI on a TOF mass analyDzeOrI.: 1M0.e10lt3in9/gC9pOoBin0t1s39a6rBe
uncorrected. Column chromatography was performed on silica gel
(300-400 mesh). Substrates 1 was prepared by reference to our
previous procedures and related literature methods.17, 20
BPO, 100 o
36 h, Ar
C
+
(1)
(2)
O
O
2a
3aa
, 61% yield
1a
, 1.07 g
General procedure for the synthesis of products 3 or 4
BPO, 100 o
C
An oven-dried Schlenk tube (25 mL) was charged with 2-(vinyloxy)-
1,1'-biphenyl (1a, 0.2 mmol), BPO (3 equiv.) and cyclohexane (2a, 2
mL). The reaction mixture was stirred under Ar atmosphere at 100
℃ for 24 h. After the reaction was completed, the resulting solution
was diluted with water (10 mL), extracted with CH2Cl2 (15 mL × 3).
The combined organic layers were washed with brine (15 mL), dried
over anhydrous Na2SO4, filtered and concentrated in vacuo. The
residue was purified by silica gel chromatography using
hexane/ethyl acetate (100:1) as eluent to give the desired product
3aa.
Ar, 24 h, Benzene
O
O
5
1a
N
standard conditions
TEMPO
(3)
O
+
+
(2 equiv.)
O
O
6
1a
2a
3aa
, 0%
Detected by GC-MS
6-(Cyclohexylmethyl)-6H-benzo[c]chromene (3aa). Yellow oil
(38.9 mg, 70% yield); H NMR (400 MHz, CDCl3): δ (ppm) 7.80–7.71
1
Scheme 4 Gram scale reaction and control experiments.
(m, 2H), 7.39 (td, J = 7.6, 1.3 Hz, 1H), 7.31 (td, J = 7.5, 1.3 Hz, 1H),
7.27 (dd, J = 7.7, 1.3 Hz, 1H), 7.14 (d, J = 7.4 Hz, 1H), 7.07 (td, J = 7.6,
1.2 Hz, 1H), 7.03 (dd, J = 8.0, 1.0 Hz, 1H), 5.31 (dd, J = 10.2, 4.1 Hz,
1H), 2.00–1.88 (m, 2H), 1.82–1.60 (m, 5H), 1.52–1.41 (m, 1H), 1.39–
1.14 (m, 3H), 1.05–0.93 (m, 2H); 13C NMR (100 MHz, CDCl3): δ (ppm)
152.7, 135.5, 129.4, 129.0, 127.9, 127.6, 124.6, 122.9, 122.6, 122.1,
121.7, 118.1, 75.2, 42.2, 33.94, 33.92, 32.6, 26.6, 26.3, 26.2; HRMS
(ESI) m/z calcd for C20H22O (M+H)+ 279.1743, found 279.1744.
6-(Cyclohexylmethyl)-8-methyl-6H-benzo[c]chromene (3ab).
Based on the above results and previous studies,18,19 a proposed
mechanism for the addition cascade cyclization of diaryl vinyl ether
1a with cyclohexane was presented in Scheme 5. Firstly, thermal
19b,c
decomposition of BPO produced benzoyloxy radical A,
which
underwent hydrogen atom transfer with cyclohexane to generate
cyclohexyl radical B. Subsequently, the addition of radical B to the
C=C double bond of 1a formed radical intermediate C, followed by
the intramolecular cyclization on benzene ring to produce radical
intermediate D. The oxidation of D by benzoyloxy radical A gave the
carbocation E. Finally, the product 3aa was produced via
deprotonation of intermediate E.
1
Yellow oil (43.9 mg, 75% yield); H NMR (400 MHz, CDCl3): δ (ppm)
7.73 (dd, J = 7.7, 1.4 Hz, 1H), 7.64 (d, J = 7.9 Hz, 1H), 7.24 (td, J = 8.0,
1.5 Hz, 1H), 7.19 (d, J = 7.9 Hz, 1H), 7.05 (td, J = 7.6, 1.1 Hz, 1H),
7.03–6.98 (m, 1H), 6.95 (s, 1H), 5.27 (dd, J = 10.4, 3.8 Hz, 1H), 2.41
(s, 3H), 2.03–1.86 (m, 2H), 1.82–1.60 (m, 5H), 1.45–1.32 (m, 4H),
1.21–0.99 (m, 2H); 13C NMR (100 MHz, CDCl3): δ (ppm) 152.5, 137.5,
135.6, 128.9, 128.7, 126.2, 125.2, 122.8, 122.7, 122.1, 121.6, 118.0,
75.3, 42.4, 33.9, 32.56, 26.6, 26.4, 26.2, 21.4; HRMS (ESI) m/z calcd
for C21H24O (M+H)+ 293.1900, found 293.1895.
O
1a

O
Ph
PhCOO
Ph
O
A
O
O
B
C
PhCOOH
PhCOO-
PhCOO
- H+
6-(Cyclohexylmethyl)-10-methyl-6H-benzo[c]chromene (3ac).
Pale yellow oil (42.7 mg, 73% yield); H NMR (400 MHz, CDCl3): δ
O
3aa
O
O
1
D
E
(ppm) 7.82 (dd, J = 8.4, 1.4 Hz, 1H), 7.31–7.22 (m, 3H), 7.10 (t, J =
7.3 Hz, 2H), 7.04 (dd, J = 5.9, 2.8 Hz, 1H), 5.19 (dd, J = 10.1, 4.3 Hz,
1H), 2.70 (s, 3H), 1.95 (d, J = 11.5 Hz, 1H), 1.89–1.70 (m, 6H), 1.63–
1.47(m, 1H), 1.35–1.31 (m, 3H), 1.05–0.91 (m, 2H); 13C NMR (100
MHz, CDCl3): δ (ppm) 154.1, 138.3, 134.3, 131.7, 128.6, 128.3,
127.6, 127.1, 124.2, 122.5, 121.0, 118.2, 76.1, 40.8, 34.0, 33.9, 32.6,
26.6, 26.3, 26.2, 23.4; HRMS (ESI) m/z calcd for C21H24O (M+H)+
293.1900, found 293.1894.
Scheme 5 Proposed mechanism.
Experimental section
General remarks
All reactions were run in a sealed tube with a Teflon lined cap under
ambient Ar atmosphere. All commercially available reagent grade
chemicals were used as received without further purification.1H
NMR (400 MHz) spectra were recorded on a Bruker Avance 400
8-(tert-Butyl)-6-(cyclohexylmethyl)-6H-benzo[c]chromene
(3ad). Pale yellow oil (46.8. mg, 70% yield); 1H NMR (400 MHz,
CDCl3): δ (ppm) 7.75 (d, J = 7.7 Hz, 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.43
(dd, J = 8.2, 1.8 Hz, 1H), 7.28–7.22 (m, 1H), 7.14 (d, J = 1.5 Hz, 1H),
7.06 (t, J = 7.5 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 5.33 (dd, J = 10.0, 4.4
Hz, 1H), 2.00–1.87 (m, 2H), 1.83–1.60 (m, 5H), 1.49–1.43 (m, 1H),
1.40 (s, 9H), 1.34–1.16 (m, 3H), 1.01–0.98 (m, 2H); 13C NMR (100
MHz, CDCl3): δ (ppm) 152.5, 150.7, 135.1, 129.0, 126.2, 124.9,
122.7, 122.6, 121.9, 121.6, 118.0, 75.6, 42.3, 34.7, 34.0, 33.9, 32.7,
1
spectrometer in CDCl3 [using (CH3)4Si (for H, δ = 0.00) as internal
standard]. 13C NMR (100 MHz) spectra on a Bruker Avance 400
spectrometer in CDCl3 [using CDCl3 (for 13C, δ = 77.00) as internal
standard]. The following abbreviations were used to explain the
multiplicities: s = singlet, d = doublet, dd = doublet of doublet, t =
triplet, dt = doublet of triplet, td = triplet of doublet, q = quartet, m
= multiplet, ddd = doublet of doublet of doublet. High-resolution
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 8
Organic & Biomolecular Chemistry
Please do not adjust margins
Journal Name
ARTICLE
31.3, 26.6, 26.4, 26.2; HRMS (ESI) m/z calcd for C24H30O (M+H)+ (ppm) -62.4; HRMS (ESI) m/z calcd for C21H21F3O (M+H)+ 347.1617,
View Article Online
DOI: 10.1039/C9OB01396B
335.2369, found 335.2365.
found 347.1615.
6-(Cyclohexylmethyl)-9-methoxy-6H-benzo[c]chromene (3ae).
6-(Cyclohexylmethyl)-8-(trifluoromethoxy)-6H-
Yellow solid (52.4 mg, 85% yield) ; mp 55–56 oC; 1H NMR (400 MHz, benzo[c]chromene (3aj). Pale yellow oil (39.9 mg, 55% yield); 1H
CDCl3): δ (ppm) 7.74 (dd, J = 7.7, 1.5 Hz, 1H), 7.39–7.31 (m, 2H), NMR (400 MHz, CDCl3): δ (ppm) 7.77–7.69 (m, 2H), 7.34–7.26 (m,
7.27 (td, J = 7.8, 1.5 Hz, 1H), 7.08–7.01 (m, 2H), 6.85 (dd, J = 7.7, 1.2 1H), 7.23 (d, J = 8.4 Hz, 1H), 7.08 (t, J = 7.5 Hz, 1H), 7.06–6.99 (m,
Hz, 1H), 5.77 (dd, J = 10.4, 3.3 Hz, 1H), 3.89 (s, 3H), 2.08–2.00 (m, 2H), 5.28 (dd, J = 10.2, 4.2 Hz, 1H), 1.93 (dt, J = 8.8, 4.8 Hz, 2H),
1H), 1.83–1.72 (m, 2H), 1.69 (m, 4H), 1.37–1.29 (m, 3H), 1.26–1.23 1.78–1.69 (m, 4H), 1.49–1.42 (m, 1H), 1.38–1.18 (m, 4H), 1.04–0.93
(m, 1H), 1.08–0.92 (m, 2H); 13C NMR (100 MHz, CDCl3): δ (ppm) (m, 2H); 13C NMR (100 MHz, CDCl3): δ (ppm) 152.6, 148.6, 137.3,
154.6, 152.4, 129. 9, 129.5, 128.3, 124.3, 123.3, 122.4, 121.4, 118.3, 129.9, 128.0, 123.7, 123.0, 121.9, 121.6, 120.5, 119.3, 118.2, 117.3,
114.5, 109.4, 70.3, 55.5, 40.7, 34.2, 33.9, 32.4, 26.7, 26.4, 26.2; 74.8, 41.8, 33.9, 32.6, 26.6, 26.3, 26.2; 19F NMR (376 MHz, CDCl3): δ
HRMS (ESI) m/z calcd for C21H24O2 (M+H)+ 309.1849, found (ppm) -57.8; HRMS (ESI) m/z calcd for C21H21F3O2 (M+H)+ 363.1566,
309.1852.
6-(Cyclohexylmethyl)-8-fluoro-6H-benzo[c]chromene
found 363.1561.
(3af).
6-(Cyclohexylmethyl)-6H-benzo[c]chromene-8-carbonitrile
Yellow oil (35.6 mg, 60% yield); 1H NMR (400 MHz, CDCl3): δ (ppm) (3ak). Pale yellow oil (27.3 mg, 45% yield); 1H NMR (400 MHz,
7.72–7.66 (m, 2H), 7.26 (td, J = 8.3, 1.9 Hz, 1H), 7.10–7.04 (m, 2H), CDCl3): δ (ppm) 7.78 (d, J = 8.1 Hz, 1H), 7.74 (dd, J = 7.8, 1.6 Hz, 1H),
7.02 (dd, J = 8.1, 1.1 Hz, 1H), 6.86 (dd, J = 8.8, 2.6 Hz, 1H), 5.25 (dd, J 7.64 (dd, J = 8.1, 1.7 Hz, 1H), 7.41 (d, J = 1.7 Hz, 1H), 7.38–7.32 (m,
= 10.2, 4.0 Hz, 1H), 1.91 (dt, J = 14.2, 5.1 Hz, 2H), 1.77–1.68 (m, 4H), 1H), 7.13–7.07 (m, 1H), 7.03 (d, J = 8.2 Hz, 1H), 5.29 (dd, J = 10.3,
1.44 (ddd, J = 14.1, 8.4, 4.0 Hz, 1H), 1.38–1.17 (m, 4H), 1.02–0.93 4.1 Hz, 1H), 1.92 (dt, J = 9.5, 5.5 Hz, 2H), 1.77–1.69 (m, 4H), 1.46–
(m, 2H); 13C NMR (100 MHz, CDCl3): δ (ppm) 162.4 (d, J = 247.2 Hz), 1.40 (m, 1H), 1.37–1.28 (m, 4H), 1.03–0.92 (m, 2H); 13C NMR (100
152.3, 137.8 (d, J = 6.9 Hz), 129.4, 125.4 (d, J = 3.1 Hz), 124.0 (d, J = MHz, CDCl3): δ (ppm) 153.4, 136.2, 133.8, 131.7, 131.4, 128.3,
8.2 Hz), 122.7, 122.0, 121.9, 118.1, 114.9 (d, J = 21.7 Hz), 111.6 (d, J 123.7, 122.8, 122.2, 120.9, 118.9, 118.5, 110.8, 74.5, 41.8, 33.9,
= 22.3 Hz), 74.8 (d, J = 1.9 Hz), 41.8, 33.9, 33.8, 32.5, 26.6, 26.3, 33.8, 32.5, 26.5, 26.3, 26.1; HRMS (ESI) m/z calcd for C21H21NO
26.1; 19F NMR (376 MHz, CDCl3): δ (ppm) -114.1; HRMS (ESI) m/z (M+H)+ 304.1696, found 304.1695.
calcd for C20H21FO (M+H)+ 297.1649, found 297.1648.
1-(6-(Cyclohexylmethyl)-6H-benzo[c]chromen-8-yl)ethan-1-
(3ag). one (3al). Yellow oil (27.6 mg, 43% yield); 1H NMR (400 MHz, CDCl3):
8-Chloro-6-(cyclohexylmethyl)-6H-benzo[c]chromene
1
Yellow oil (40.7 mg, 65% yield); H NMR (400 MHz, CDCl3): δ (ppm) δ (ppm) 7.93 (dd, J = 8.2, 1.7 Hz, 1H), 7.79–7.75 (m, 2H), 7.73 (d, J =
7.70 (dd, J = 7.7, 1.4 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.34 (dd, J = 1.4 Hz, 1H), 7.32 (td, J = 8.1, 1.5 Hz, 1H), 7.07 (td, J = 7.6, 1.1 Hz,
8.3, 2.1 Hz, 1H), 7.28 (ddd, J = 8.9, 7.2, 1.5 Hz, 1H), 7.12 (d, J = 2.0 1H), 7.02 (dd, J = 8.1, 0.9 Hz, 1H), 5.35 (dd, J = 10.5, 3.8 Hz, 1H), 2.64
Hz, 1H), 7.06 (td, J = 7.6, 1.1 Hz, 1H), 7.04–6.97 (m, 1H), 5.24 (dd, J = (s, 3H), 1.97–1.88 (m, 2H), 1.75–1.66 (m, 4H), 1.48–1.41 (m, 1H),
10.5, 3.8 Hz, 1H), 1.97–1.90 (m, 2H), 1.72 (d, J = 9.8 Hz, 4H), 1.46– 1.37–1.13 (m, 4H), 1.04–0.92 (m, 2H); 13C NMR (100 MHz, CDCl3): δ
1.40 (m, 1H), 1.36–1.17 (m, 4H), 0.99 (td, J = 12.3, 2.8 Hz, 2H); 13C (ppm) 197.4, 153.4, 136.0, 135.7, 133.8, 130.9, 128.3, 124.6, 123.7,
NMR (100 MHz, CDCl3): δ (ppm) 152.5, 137.2, 133.3, 129.8, 128.0, 122.2, 121.9, 121.5, 118.4, 75.1, 42.1, 34.0, 33.9, 32.5, 26.7, 26.6,
127.7, 124.7, 123.6, 122.9, 121.9, 121.7, 118.1, 74.7, 41.9, 34.0, 26.3, 26.2; HRMS (ESI) m/z calcd for C22H24O2 (M+H)+ 321.1849,
33.9, 32.5, 26.6, 26.3, 26.1; HRMS (ESI) m/z calcd for C20H21ClO found 321.1849.
(M+H)+ 313.1354, found 313.1357.
6-(Cyclohexylmethyl)-6H-benzo[c]chromene-8-carbaldehyde
(3ah). (3am). Pale yellow oil (24.5 mg, 40% yield); 1H NMR (400 MHz,
8-Bromo-6-(cyclohexylmethyl)-6H-benzo[c]chromene
1
Pale yellow oil (48.6 mg, 68% yield); H NMR (400 MHz, CDCl3): δ CDCl3): δ (ppm) 10.02 (s, 1H), 7.86 (d, J = 0.8 Hz, 2H), 7.79 (dd, J =
(ppm) 7.70 (dd, J = 7.8, 1.5 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.49 (dd, 7.8, 1.4 Hz, 1H), 7.66 (s, 1H), 7.36–7.31 (m, 1H), 7.09 (td, J = 7.6, 1.0
J = 8.3, 2.0 Hz, 1H), 7.31–7.26 (m, 2H), 7.06 (td, J = 7.6, 1.2 Hz, 1H), Hz, 1H), 7.04 (dd, J = 8.1, 0.9 Hz, 1H), 5.36 (dd, J = 10.5, 3.8 Hz, 1H),
7.01 (dd, J = 8.1, 1.1 Hz, 1H), 5.24 (dd, J = 10.5, 3.8 Hz, 1H), 1.97– 1.99–1.92 (m, 2H), 1.76–1.68 (m, 4H), 1.52–1.48 (m, 1H), 1.35–1.25
1.89 (m, 2H), 1.72 (d, J = 9.7 Hz, 4H), 1.45–1.39 (m, 1H), 1.37–1.17 (m, 4H), 1.04–0.95 (m, 2H); 13C NMR (100 MHz, CDCl3): δ (ppm)
(m, 4H), 1.03–0.92 (m, 2H); 13C NMR (100 MHz, CDCl3): δ (ppm) 191.6, 153.6, 136.1, 135.4, 135.2, 131.2, 130.1, 125.5, 123.9, 122.7,
152.6, 137.5, 131.0, 129.9, 128.2, 127.6, 123.9, 122.9, 121.9, 121.8, 122.1, 121.5, 118.4, 74.9, 41.9, 34.0, 33.9, 32.5, 26.5, 26.3, 26.2;
121.4, 118.2, 74.6, 41.9, 33.9, 33.8, 32.5, 26.6, 26.3, 26.2; HRMS HRMS (ESI) m/z calcd for C21H22O2 (M+H)+ 307.1692, found
(ESI) m/z calcd for C20H21BrO (M+H)+ 357.0849, found 357.0843.
307.1693.
6-(Cyclohexylmethyl)-2-methyl-6H-benzo[c]chromene (3an).
6-(Cyclohexylmethyl)-8-(trifluoromethyl)-6H-
1
benzo[c]chromene (3ai). Pale yellow solid (34.6 mg, 50% yield); mp Pale yellow oil (42.7 mg, 73% yield); H NMR (400 MHz, CDCl3): δ
55–56 oC; 1H NMR (400 MHz, CDCl3): δ (ppm) 7.81 (d, J = 8.2 Hz, 1H), (ppm) 7.73 (dd, J = 7.8, 1.2 Hz, 1H), 7.56 (d, J = 2.0 Hz, 1H), 7.37 (td,
7.76 (dd, J = 7.8, 1.5 Hz, 1H), 7.65–7.59 (m, 1H), 7.38 (s, 1H), 7.33 J = 7.6, 1.4 Hz, 1H), 7.30 (td, J = 7.5, 1.9 Hz, 1H), 7.12 (dd, J = 7.5, 1.3
(td, J = 8.1, 1.6 Hz, 1H), 7.09 (td, J = 7.6, 1.2 Hz, 1H), 7.04 (dd, J = 8.1, Hz, 1H), 7.08 (dd, J = 8.2, 2.1 Hz, 1H), 6.92 (d, J = 8.1 Hz, 1H), 5.27
1.1 Hz, 1H), 5.34 (dd, J = 10.5, 3.8 Hz, 1H), 2.01–1.91 (m, 2H), 1.77– (dd, J = 10.2, 4.2 Hz, 1H), 2.40 (s, 3H), 1.98–1.86 (m, 2H), 1.78–1.68
1.68 (m, 4H), 1.44 (ddd, J = 14.1, 8.6, 3.9 Hz, 1H), 1.39–1.13 (m, 4H), (m, 4H), 1.46–1.38 (m, 1H), 1.35–1.21 (m, 4H), 1.03–0.91 (m, 2H);
1.00 (m, 2H); 13C NMR (100 MHz, CDCl3): δ (ppm) 153.2, 135.9, 13C NMR (100 MHz, CDCl3): δ (ppm) 150.5, 135.7, 130.8, 130.1,
132.7, 132.7, 130.7, 129.4 (q, J = 32.5 Hz), 124.8 (q, J = 3.7 Hz), 129.2, 127.9, 127.5, 124.7, 123.4, 122.2, 122.1, 117.8, 75.2, 42.1,
123.5, 122.5, 122.0, 121.6 (q, J = 3.9 Hz), 121.3, 118.3, 74.9, 41.9, 34.0, 33.9, 32.6, 26.6, 26.3, 26.2, 21.0; HRMS (ESI) m/z calcd for
34.0, 33.9, 32.4, 26.5, 26.3, 26.1; 19F NMR (376 MHz, CDCl3): δ C21H24O (M+Na)+ 315.1719, found 315.1723.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 6 of 8
ARTICLE
Journal Name
6-(Cyclopentylmethyl)-6H-benzo[c]chromene (3ba). Yellow oil 42.4, 33.1, 32.9, 30.9, 27.5, 27.4, 26.3, 25.3, 25.2; HRMS (ESI) m/z
View Article Online
1
(37.5 mg, 55% yield); H NMR (400 MHz, CDCl3): δ (ppm) 7.79–7.73 calcd for C22H25ClO (M+H)+ 341.1667, found D3O41I:.1106.61063.9/C9OB01396B
(m, 2H), 7.39 (td, J = 7.6, 1.3 Hz, 1H), 7.32 (td, J = 7.5, 1.2 Hz, 1H),
6-(2-Ethylbutyl)-6H-benzo[c]chromene (3da). Pale yellow oil
7.29–7.25 (m, 1H), 7.18–7.14 (m, 1H), 7.08 (td, J = 7.5, 1.1 Hz, 1H), (41.2 mg, complex mixture, 66% yield); 1H NMR (400 MHz, CDCl3): δ
7.03 (d, J = 8.0 Hz, 1H), 5.23 (dd, J = 9.4, 4.7 Hz, 1H), 2.15–2.01 (m, (ppm) 7.78–7.73 (m, 2H), 7.38 (td, J = 7.6, 1.4 Hz, 1H), 7.34–7.24 (m,
2H), 1.96–1.86 (m, 2H), 1.68–1.53 (m, 5H), 1.23–1.12 (m, 2H); 13C 2H), 7.14 (dd, J = 7.5, 1.4 Hz, 1H), 7.07 (td, J = 7.6, 1.2 Hz, 1H), 7.01
NMR (100 MHz, CDCl3): δ (ppm) 152.8, 135.3, 129.5, 128.9, 128.01, (dd, J = 8.1, 1.3 Hz, 1H), 5.32–5.25 (m, 1H), 2.09–1.76 (m, 2H), 1.50–
127.6, 124.8, 122.9, 122.5, 122.2, 121.7, 118.1, 77.3, 41.0, 36.6, 1.37 (m, 2H), 1.32–1.24 (m, 3H), 1.06 (d, J = 6.6 Hz, 1H), 0.98 (d, J =
33.0, 32.5, 25.2, 25.0; HRMS (ESI) m/z calcd for C19H20O (M+H)+ 6.5 Hz, 1H), 0.95–0.91 (m, 2H), 0.89–0.85 (m, 1H), 0.81 (t, J = 7.4 Hz,
265.1587, found 265.1584.
1H); 13C NMR (100 MHz, CDCl3): δ (ppm) 152.8, 152.7, 135.7, 135.4,
8-(tert-Butyl)-6-(cyclopentylmethyl)-6H-benzo[c]chromene
129.5, 129.1, 129.0, 128.9, 128.0, 127.9, 127.7, 127.6, 127.5, 124.7,
(3bb). Pale yellow oil (61.8 mg, 86% yield); 1H NMR (400 MHz, 124.6, 124.5, 122.9, 122.7, 122.6, 122.5, 122.2, 122.1, 122.1, 121.8,
CDCl3): δ (ppm) 7.74 (dd, J = 7.7, 1.6 Hz, 1H), 7.68 (d, J = 8.2 Hz, 1H), 121.7, 121.6, 75.9, 75.8, 75.4, 42.1, 41.7, 39.7, 38.5, 38.2, 36.4,
7.42 (dd, J = 8.2, 2.0 Hz, 1H), 7.24 (ddd, J = 7.9, 7.3, 1.6 Hz, 1H), 7.15 29.7, 29.2, 28.7, 25.6, 24.8, 20.2, 19.9, 19.8, 19.2, 14.3, 14.2, 10.8,
(d, J = 2.0 Hz, 1H), 7.08–6.98 (m, 2H), 5.22 (dd, J = 9.4, 4.6 Hz, 1H), 10.4.; HRMS (ESI) m/z calcd for C19H22O (M+H)+ 267.1743, found
2.12–2.00 (m, 2H), 1.97–1.87 (m, 2H), 1.68–1.57 (m, 5H), 1.39 (s, 267.1749.
9H), 1.23–1.14 (m, 2H); 13C NMR (100 MHz, CDCl3): δ (ppm) 152.5,
6-(2-Ethylpentyl)-6H-benzo[c]chromene (3ea). Pale yellow oil
150.8, 134.9, 128.9, 126.1, 124.9, 122.7, 122.6, 121.9, 121.7, 121.5, (45.1 mg, complex mixture, 60% yield); 1H NMR (400 MHz, CDCl3): δ
117.9, 77.7, 41.1, 36.7, 34.7, 33.0, 32.5, 31.3, 25.2, 24.9; HRMS (ESI) (ppm) 7.76 (ddd, J = 7.5, 6.1, 1.4 Hz, 2H), 7.39 (td, J = 7.6, 1.4 Hz,
m/z calcd for C23H28O (M+H)+ 321.2213, found 321.2217.
1H), 7.32 (dd, J = 7.5, 1.2 Hz, 1H), 7.29–7.25 (m, 1H), 7.15 (dd, J =
8-Chloro-6-(cyclopentylmethyl)-6H-benzo[c]chromene (3bc). 7.5, 1.5 Hz, 1H), 7.07 (tt, J = 7.5, 1.2 Hz, 1H), 7.01 (dt, J = 7.9, 1.1 Hz,
1
Yellow oil (43.8 mg, 60% yield); H NMR (400 MHz, CDCl3): δ (ppm) 1H), 5.32–5.25 (m, 1H), 2.09–1.81 (m, 2H), 1.49–1.42 (m, 1H), 1.34–
7.70 (dd, J = 7.8, 1.6 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.34 (dd, J = 1.22 (m, 5H), 1.07 (d, J = 6.6 Hz, 1H), 0.99 (d, J = 6.6 Hz, 1H), 0.96–
8.3, 2.2 Hz, 1H), 7.27 (dd, J = 8.0, 1.6 Hz, 1H), 7.14 (d, J = 2.0 Hz, 1H), 0.92 (m, 2H), 0.91–0.87 (m, 2H), 0.82 (t, J = 7.4 Hz, 1H). 13C NMR
7.07 (td, J = 7.5, 1.3 Hz, 1H), 7.02 (dd, J = 8.1, 1.3 Hz, 1H), 5.16 (dd, J (100 MHz, CDCl3): δ (ppm) 152.7, 152.6, 135.7, 135.6, 135.4, 129.5,
= 9.6, 4.4 Hz, 1H), 2.13–2.00 (m, 2H), 1.94–1.85 (m, 2H), 1.68–1.57 129.4, 129.2, 129.1, 129.0, 128.0, 127.9, 127.7, 127.6, 127.5, 124.8,
(m, 5H), 1.22–1.10 (m, 2H); 13C NMR (100 MHz, CDCl3): δ (ppm) 124.7, 124.6, 124.5, 123.0, 122.9, 122.7, 122.6, 122.5, 122.2, 122.1,
152.6, 136.9, 133.3, 129.8, 128.1, 127.6, 124.9, 123.6, 122.9, 121.9, 121.8, 121.7, 121.6, 118.2, 118.1, 75.9, 75.8, 75.7, 75.4, 42.1, 41.8,
121.7, 118.2, 76.7, 40.8, 36.5, 33.1, 32.4, 25.2, 25.0; HRMS (ESI) m/z 38.7, 38.6, 37.2, 35.9, 35.6, 35.1, 35.0, 34.7, 34.6, 31.8, 29.4, 29.2,
calcd for C19H19ClO (M+H)+ 299.1197, found 299.1195.
29.1, 29.0, 28.9, 26.3, 25.6, 25.3, 23.0, 22.9, 22.7, 20.2, 19.7, 19.6,
6-(Cyclooctylmethyl)-6H-benzo[c]chromene (3ca). Yellow oil 19.3, 14.6, 14.4, 14.2, 14.1, 10.8, 10.4; HRMS (ESI) m/z calcd for
(38.0 mg, 62% yield); 1H NMR (400 MHz, CDCl3): δ (ppm) 7.77 (t, J = C20H24O (M+H)+ 281.1900, found 281.1893.
7.2 Hz, 2H), 7.40 (t, J = 7.6 Hz, 1H), 7.35–7.26 (m, 2H), 7.16 (d, J =
6-(Cyclohexylmethyl)-6H-benzo[c]thiochromene (4a). Yellow
1
7.3 Hz, 1H), 7.11–7.01 (m, 2H), 5.29 (dd, J = 9.8, 4.1 Hz, 1H), 1.97– oil (56.8 mg, 60% yield); H NMR (400 MHz, CDCl3): δ (ppm) 7.83
1.83 (m, 4H), 1.70–1.64 (m, 5H), 1.59–1.52 (m, 5H), 1.44–1.31 (m, (dd, J = 7.4, 1.8 Hz, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.46–7.43 (m, 1H),
3H); 13C NMR (100 MHz, CDCl3): δ (ppm) 152.8, 135.6, 129.5, 129.1, 7.39 (td, J = 7.5, 1.5 Hz, 1H), 7.36–7.31 (m, 1H), 7.30–7.25 (m, 2H),
127.9, 127.6, 124.7, 123.0, 122.7, 122.2, 121.7, 118.1, 75.6, 42.7, 7.24–7.19 (m, 1H), 3.92 (dd, J = 8.7, 6.6 Hz, 1H), 1.75–1.59 (m, 7H),
33.1, 32.9, 31.1, 27.5, 27.4, 26.4, 25.4, 25.3; HRMS (ESI) m/z calcd 1.50–1.44 (m, 1H), 1.30–1.18 (m, 3H), 0.95–0.80 (m, 2H); 13C NMR
for C22H26O (M+H)+ 307.2056, found 307.2054.
(100 MHz, CDCl3): δ (ppm) 137.9, 134.1, 133.1, 131.4, 129.3, 127.9,
8-(tert-Butyl)-6-(cyclooctylmethyl)-6H-benzo[c]chromene
127.8, 127.5, 126.6, 126.4, 126.2, 125.2, 42.0, 41.6, 34.5, 33.5, 32.6,
1
(3cb). Yellow oil (68.7 mg, 57% yield); H NMR (400 MHz, CDCl3): δ 26.6, 26.2, 26.1; HRMS (ESI) m/z calcd for C20H22S (M+H)+ 295.1515,
(ppm) 7.77–7.67 (m, 2H), 7.43 (dd, J = 8.2, 2.1 Hz, 1H), 7.29–7.22 found 295.1518.
(m, 1H), 7.15 (d, J = 2.1 Hz, 1H), 7.09–7.00 (m, 2H), 5.28 (dd, J = 9.5,
1-(6-(Cyclohexylmethyl)-6H-benzo[c]thiochromen-8-yl)ethan-
4.6 Hz, 1H), 1.96–1.80 (m, 4H), 1.70–1.62 (m, 5H), 1.61–1.47 (m, 1-one (4b). Yellow oil (45.1 mg, 45% yield); 1H NMR (400 MHz,
8H), 1.40 (s, 9H); 13C NMR (100 MHz, CDCl3): δ (ppm) 152.6, 150.8, CDCl3): δ (ppm) 7.95 (dd, J = 8.2, 1.8 Hz, 1H), 7.88–7.84 (m, 1H),
135.2, 129.1, 126.3, 125.0, 122.8, 122.7, 121.9, 121.7, 121.6, 118.0, 7.82 (dd, J = 5.0, 3.1 Hz, 2H), 7.48–7.45 (m, 1H), 7.33–7.30 (m, 2H),
76.0, 43.0, 34.7, 33.1, 32.9, 31.5, 31.4, 27.4, 27.3, 26.4, 25.6, 25.4; 3.99 (dd, J = 9.3, 5.8 Hz, 1H), 2.66 (s, 3H), 1.71–1.60 (m, 7H), 1.52–
HRMS (ESI) m/z calcd for C26H34O (M+H)+ 363.2682, found 1.47 (m, 1H), 1.30–1.21 (m, 3H), 0.94–0.83 (m, 2H); 13C NMR (100
363.2678.
8-Chloro-6-(cyclooctylmethyl)-6H-benzo[c]chromene
Yellow oil (51.2 mg, 69% yield); H NMR (400 MHz, CDCl3): δ (ppm) 26.5, 26.2, 26.0; HRMS (ESI) m/z calcd for C22H24OS (M+H)+
7.70 (dd, J = 7.8, 1.6 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.34 (dd, J = 337.1620, found 337.1620.
8.4, 2.2 Hz, 1H), 7.28 (td, J = 7.8, 1.6 Hz, 1H), 7.15–7.12 (m, 1H), 7.07
MHz, CDCl3): δ (ppm) 197.6, 138.2, 137.6, 136.1, 133.2, 132.3,
(3cc). 129.5, 128.9, 127.5, 126.6, 126.4, 125.8, 41.6, 34.5, 33.6, 32.5, 26.7,
1
(td, J = 7.5, 1.3 Hz, 1H), 7.02 (dd, J = 8.1, 1.3 Hz, 1H), 5.21 (dd, J =
10.3, 3.9 Hz, 1H), 2.01–1.83 (m, 4H), 1.73–1.60 (m, 8H), 1.58–1.51
(m, 5H); 13C NMR (100 MHz, CDCl3): δ (ppm) 152.6, 137.3, 133.3,
Conclusions
In summary, we developed
a new radical addition cascade
129.8, 128.1, 127.8, 124.7, 123.6, 122.9, 121.9, 121.8, 118.1, 75.1,
intramolecular cyclization/aromatization of diaryl vinyl ethers with
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 7 of 8
Organic & Biomolecular Chemistry
Please do not adjust margins
Journal Name
ARTICLE
9
D. Killander and O. Sterner, Eur. J. Org. Chem., 2014,
unactivated alkanes for accessing 6-alkyl-6H-benzo[c]chromenes.
The obvious advantage of our method is the simple reaction
conditions. It did not employ costly transition-metal catalysts and
strong base. Moreover, 6-alkyl-6H-benzo[c]thiochromenes could
also been obtained by using diaryl vinyl thioethers as the
substrates. We were optimistic that this work would find use in
medicinal chemistry through the construction of oxygen-containing
or sulfur-containing fused heterocyclic compounds.
View Article Online
1594−1596.
DOI: 10.1039/C9OB01396B
10 J. W. Lee, S. Bae and W. H. Jo, J. Mater. Chem. A, 2014, 2,
14146−14153.
11 (a) L.-C. Campeau, M. Parisien, M. Leblanc and K. Fagnou, J.
Am. Chem. Soc., 2004, 126, 9186−9187; (b) L.-C. Campeau,
M. Parisien, A. Jean and K. Fagnou, J. Am. Chem. Soc., 2006,
128, 581−590; (c) M. Lafrance, D. Lapointe and K. Fagnou,
Tetrahedron, 2008, 64, 6015−6020; (d) R. Cano, J. M. Perez,
D. J. Ramon and G. P. McGlacken, Tetrahedron, 2016, 72,
1043−1050.
12 W. Liu, H. Cao, J. Xin, L. Jin and A. Lei, Chem. -Eur. J., 2011,
17, 3588−3592.
13 C.-L. Sun, Y.-F. Gu, W.-P. Huang and Z.-J. Shi, Chem.
Commun., 2011, 47, 9813−9815.
14 J. Zhou, L.-Z. Huang, Y.-Q. Li and Z.-T. Du, Tetrahedron Lett.,
2012, 53, 7036−7039.
Conflicts of interest
There are no conflicts to declare.
15 Z. Shen, Z. Ni, S. Mo, J. Wang and Y. Zhu, Chem. -Eur. J. 2012,
18, 4859−4865.
16 (a) A. Ahmed, S. Dhara and J. K. Ray, Tetrahedron Lett., 2013,
54, 1673−1676; (b) R. Singha, A. Ahmed, Y. Nuree, M. Ghosh
and J. K. Ray, RSC Adv., 2015, 5, 50174−50177.
17 Q. Deng, L. Tan, Y. Xu, P. Liu and P. Sun, J. Org. Chem., 2018,
83, 6151−6161.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (Project 21672104, 21502097), the
Natural Science Foundation of the Education Department of
Jiangsu province (15KJB150015), and the Priority Academic
Program Development of Jiangsu Higher Education
Institutions. The authors also thank Mr. Hailong Liu for the
determination of HRMS.
18 J. Ji, P. Liu and P. Sun, Chem. Commun., 2015, 51,
7546−7549.
19 (a) Y.-J. Jang, Y.-K. Shih, J.-Y. Liu, W.-Y. Kuo and C.-F. Yao,
Chem. -Eur. J., 2003, 9, 2123−2128; (b) Y. Guo, Y. Xiang, L.
Wei and J.-P. Wan, Org. Lett., 2018, 20, 3971−3974; (c) J.-P.
Wan, Z. Tu and Y. Wang, Chem. -Eur. J., 2019, 25, 6907−6910.
20 W. Wu, S. Yi, W. Huang, D. Luo and H. Jiang, Org. Lett., 2017,
19, 2825−2828.
Notes and references
1
For recent reviews, see: (a) T. W. Lyons and M. S. Sanford,
Chem. Rev., 2010, 110, 1147−1169; (b) C. S. Yeung and V. M.
Dong, Chem. Rev., 2011, 111, 1215−1292; (c) Y. Segawa, T.
Maekawa and K. Itami, Angew. Chem., Int. Ed., 2015, 54,
66−81; (d) R. Shang, L. Ilies and E. Nakamura, Chem. Rev.,
2017, 117, 9086−9139; (e) J.-P. Wan, L. Gan and Y. Liu, Org.
Biomol. Chem., 2017, 15, 9031−9043.
2
3
4
C. Liu, J. Yuan, M. Gao, S. Tang, W. Li, R. Shi and A. Lei, Chem.
Rev., 2015, 115, 12138−12204.
X.-S. Xue, P. Ji, B. Zhou and J.-P. Cheng, Chem. Rev., 2017,
117, 8622−8648.
For recent reviews, see: (a) S. A. Girard, T. Knauber and C.-J.
Li, Angew. Chem., Int. Ed., 2014, 53, 74−100; (b) O. Baudoin,
Acc. Chem. Res. 2017, 50, 1114−1123; (c) J. He, M. Wasa, K.
S. L. Chan, Q. Shao and J.-Q. Yu, Chem. Rev., 2017, 117,
8754−8786; (d) J. C. K. Chu and T. Rovis, Angew. Chem., Int.
Ed., 2018, 57, 62−101; (e) Y. Xu and G. Dong, Chem. Sci.,
2018, 9, 1424−1432.
For recent reviews and examples on transition-metal-free C-
H bond functionalization, see: (a) C.-L. Sun and Z.-J. Shi,
Chem. Rev., 2014, 114, 9219−9280; (b) P. Liu, G. Zhang and P.
Sun, Org. Biomol. Chem., 2016, 14, 10763−10777; (c) J.-P.
Wan, S. Zhong, L. Xie, X. Cao, Y. Liu and L. Wei, Org. Lett.,
2016, 18, 584−587; (d) Y. Liu, J. Xiong and L. Wei, Chin. J. Org.
Chem., 2017, 37, 1667−1680; (e) Y. Wang and Y. Liu, Acta
Chim. Sinica, 2019, 77, 418−421; (f) Q.-L. Xu, H. Gao, M.
Yousufuddin, D. H. Ess and L. Kürti, J. Am. Chem. Soc., 2013,
135, 14048−14051; (g) C. D. Prasad, M. Sattar and S. Kumar,
Org. Lett., 2017, 19, 774−777.
5
6
7
Y. Qin, L. Zhu and S. Luo, Chem. Rev., 2017, 117, 9433−9520.
(a) R. Pratap and V. J. Ram, Chem. Rev., 2014, 114,
10476−10526; (b) J. Pandey, A. K. Jha and K. Hajela, Bioorg.
Med. Chem., 2004, 12, 2239−2249.
G. Appendino, S. Gibbons, A. Giana, A. Pagani, G. Grassi, M.
Stavri, E. Smith and M. M. Rahman, J. Nat. Prod., 2008, 71,
1427−1430.
8
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
Please do not adjust margins

Organic & Biomolecular Chemistry
Page 8 of 8
View Article Online
DOI: 10.1039/C9OB01396B
Graphical Abstract
BPO promoted direct oxidative C–H functionalization of unactivated alkanes
into 6-alkyl 6H-benzo[c]chromenes under transition-metal-free conditions†
Lei Ji, Qinfei Deng, Ping Liu* and Peipei Sun*
R2
R2
BPO, 100 oC
24 h, Ar
R1
R1
H
+
X
X
X = O, S
Transition-metal-free conditions
Strong base free conditions
Simple operation