Enantioselective synthesis of fluorene derivatives by chiral N-triflyl phosphoramide catalyzed double Friedel-Crafts alkylation reaction

Article abstract of DOI:10.1039/c2ob07168a

A highly efficient tandem double Friedel-Crafts reaction between indoles and 2-formylbiphenyl derivatives by chiral N-triflyl phosphoramide was realized. Under mild conditions, various 9-(3-indolyl) fluorene derivatives have been obtained in good yield and up to 94% ee. Comparing to their corresponding chiral phosphoric acids, chiral N-triflyl phosphoramides catalyzed reactions led to products with opposite absolute configuration.

Full text of DOI:10.1039/c2ob07168a

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PAPER
Enantioselective synthesis of fluorene derivatives by chiral N-triflyl
phosphoramide catalyzed double Friedel–Crafts alkylation reaction†‡
Shou-Guo Wang, Long Han, Mi Zeng, Feng-Lai Sun, Wei Zhang and Shu-Li You*
Received 23rd December 2011, Accepted 20th February 2012
DOI: 10.1039/c2ob07168a
A highly efficient tandem double Friedel–Crafts reaction between indoles and 2-formylbiphenyl
derivatives by chiral N-triflyl phosphoramide was realized. Under mild conditions, various 9-(3-indolyl)
fluorene derivatives have been obtained in good yield and up to 94% ee. Comparing to their
corresponding chiral phosphoric acids, chiral N-triflyl phosphoramides catalyzed reactions led to products
with opposite absolute configuration.
With chiral phosphoric acids as the catalysts, we recently rea-
lized a tandem double Friedel–Crafts alkylation reaction11 of
indoles with 2-formylbiphenyl derivatives, leading to 9-(3-
indolyl)-fluorene derivatives in high ees (Scheme 1).12 Interest-
ingly, the reaction features the activation of both aldehyde and
alcohol by chiral phosphoric acid and the accomplishment of
two Friedel–Crafts alkylation reactions in a tandem fashion. As
part of our ongoing efforts to develop chiral Brønsted acid-cata-
lyzed asymmetric reactions,13 we envisaged the chiral N-triflyl
phosphoramide,14 a stronger Brønsted acid than its correspond-
ing phosphoric acid, might be a more efficient catalyst in the
above asymmetric tandem double Friedel–Crafts reaction.
Notably, since the first introduction of chiral N-triflyl phosphora-
mides as efficient organocatalysts by Yamamoto and co-
workers,15 this unique class of catalysts has been applied
successfully in many asymmetric catalytic reactions.16 Indeed,
chiral N-triflyl phosphoramide was found to be an efficient cata-
lyst for the synthesis of fluorene derivatives in high ees via the
above double Friedel–Crafts alkylation reactions. Interestingly,
the products were obtained with the opposite absolute configur-
ations compared to those obtained with a chiral phosphoric acid
catalyst. In addition, the reaction catalyzed by chiral N-triflyl
phosphoramide displayed broader substrate scope. In this article,
we report the full account of this study.
Introduction
Fluorene is widely existed as the core structure of naturally
occurring or synthetic molecules.1 Some fluorene derivatives
such as BMS-201038, amyxin and compound A (Fig. 1) have
interesting biological activities and can be used as MTP inhibi-
tor, interferon inducers and antitumor compounds respectively.
Fluorenes in polymer form have also attracted much attention in
recent years due to their wide applications as advanced materials
with unique electronic and photonic properties including organic
light-emitting diodes, thin film transistors, photovoltaic cells, etc.
Despite their significant applications and extensive synthetic
studies,2 the asymmetric synthesis of fluorene derivatives has
been rarely explored but is certainly highly desirable.
The Friedel–Crafts alkylation reaction is one of the most
powerful methods to derivatize aromatic compounds by forming
carbon–carbon bond.3 Chiral phosphoric acids4 recently proved
to be efficient catalysts for the asymmetric Friedel–Crafts alky-
lation of arenes with various electrophilic partners, such as
imines,5 enamides,6 α,β-unsaturated carbonyls,7 and nitro-
olefins.8 However, the readily available alcohols have been
seldom used in asymmetric Friedel–Crafts alkylation reactions.
In 2008, Rueping and co-workers reported the first chiral N-
triflyl phosphoramide catalyzed enantioselective Friedel–Crafts
reaction of indole with alcohol, but with moderate enantioselec-
tivity.9 Notably, Gong and Rueping independently utilized alco-
hols in chiral Brønsted acid-catalyzed asymmetric alkylation of
enamide and allylic substitution reaction, respectively.10
Results and discussion
We began our study by testing various chiral phosphoramides in
the tandem double Friedel–Crafts reaction of 2a with 3a in
toluene at −15 °C. As summarized in Table 1, all the phosphora-
mides, particularly N-triflyl phosphoramides, proved to be
efficient catalysts for this reaction. In most of cases, product 4aa
was obtained in excellent conversions within 2 days. Among
these tested chiral N-triflyl phosphoramides, (S)-1f was found to
be the optimal one in terms of a combination of yield and ee
(>95% conversion, 89% ee, Table 1, entry 6). It is interesting to
State Key Laboratory of Organometallic Chemistry, Shanghai Institute
of Organic Chemistry, Chinese Academy of Science, 345 Lingling Lu,
Shanghai, 200032, China. E-mail: slyou@sioc.ac.cn; Fax: (+86) 21-
54925087
†This article is part of the joint ChemComm–Organic & Biomolecular
Chemistry ‘Organocatalysis’ web themed issue.
‡Electronic supplementary information (ESI) available. See DOI:
10.1039/c2ob07168a
3202 | Org. Biomol. Chem., 2012, 10, 3202–3209
This journal is © The Royal Society of Chemistry 2012

Fig. 1 Selected fluorene derivatives. LPPP: ladder type poly(para-phenylene).
Scheme 1 Chiral phosphoric acid catalyzed tandem double Friedel–Crafts reaction.
note that the absolute configuration of product 4aa obtained by
utilizing (S)-N-triflyl phosphoramide is R, which is opposite of
that obtained with (S)-phosphoric acid.
generality of the reaction. The results are summarized in Table 3.
In general, all the tested 2-methyl indoles with either electron-
withdrawing or electron-donating substituents reacted smoothly
to give their corresponding cyclization products 4 with satisfac-
tory enantioselectivities. However, when indole was applied,
both yield and ee of the product were significantly decreased
(Table 3, entry 8). The reaction with 2-phenyl indole proceeded
smoothly in 8% yield and 28% ee (Table 3, entry 9). Meanwhile,
the scope of 2-formylbiphenyl derivatives was also explored by
subjecting them to the optimized reaction conditions with 3a. As
shown in Scheme 2, all the desired fluorene derivatives were
obtained with good to excellent yields and enantioselectivities.
Notably, products 4fa and 4ha were synthesized for the first
With the optimal catalyst (S)-1f in hand, different reaction par-
ameters including the reaction temperature and solvent were
further optimized. As summarized in Table 2, the reaction pro-
ceeded smoothly in various solvents and o-xylene was found to
be the optimal one (92% yield, 90% ee, Table 2, entry 4). Reac-
tions at lower temperature could also proceed smoothly to com-
pletion, although the enantioselectivity slightly decreased
(Table 2, entry 7).
Under the optimized reaction conditions (Table 2, entry 4),
various substituted indoles were investigated to test the
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 3202–3209 | 3203

Table 1 Screening the 3,3′-substituents of chiral phosphoramide
Table 3 Substrate scopea
catalystsa
Entry
R1, R2
4, yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
Me, H
4aa, 92
4ab, 89
4ac, 97
4ad, 97
4ae, 38
4af, 97
4ag, 67
4ah, 35
4ai, 8
90
90
84
85
89
91
94
2
Me, 5-Me
Me, 5-Br
Me, 5-Cl
Me, 5-F
Me, 5- OCH3
Me, 7-Br
H, H
Entry
1 R1, R2
Conv.b (%)
eec (%)
1
2
3
4
5
6
7
8
1a 3,5-(CF3)2-phenyl, Tf
1b biphenyl, Tf
1c SiPh3, Tf
1d pyrenyl, Tf
1e 3,5-(CH3)2-phenyl, Tf
1f 9-anthryl, Tf
1g 9-phenanthryl, Tf
1h 4-NO2-phenyl, Tf
1i 2,4,6-(iPr)3-C6H2, Tf
1j 3,5-(CF3)2-biphenyl, Tf
1k 3,5-(CF3)2-phenyl, SO2C8F17
>95
>95
>95
>95
97
>95
>95
>95
>95
97
86
39
53
58
33
89
66
43
51
53
55
Ph, H
28
a All the reactions were performed using 0.10 mmol 2a, 0.15 mmol 3
and 100 mg 5 Å MS in 1.5 mL o-xylene with 5 mol% of catalyst (S)-1f
at −15 °C. b Isolated yield. c Determined by HPLC analysis (Chiralpak
AD-H).
9
10
11
>95
a All the reactions were performed using 0.10 mmol 2a, 0.15 mmol 3a
and 100 mg 5 Å MS in 1.5 mL toluene with 5 mol% of catalyst (S)-1 at
−15 °C. b Isolated yield for entries 5 and 10. c Determined by HPLC
analysis (Chiralpak AD-H).
Table 2 Screening reaction temperatures and solventsa
ð1Þ
When 6a and 6b were used to react with 3a under the standard
conditions, bisindole alkylated products 7a and 7b were obtained
respectively (eqn (2) and (3)). Interestingly, when the reaction
was performed at room temperature, the corresponding fluorene
derivatives could be obtained in excellent yields with moderate
enantioselectivities (eqn (4) and (5)).
Entry
Solvent
Conv.b (%)
eec (%)
1
2
3
4
Et2O
DCM
CCl4
o-Xylene
Ph-Cl
Toluene
Toluene
>95
>95
92
>95 (92)
96
>95
96
70
33
84
90
78
89
85
5
6
7d
a All the reactions were performed using 0.10 mmol 2a, 0.15 mmol 3a
and 100 mg 5 Å MS in 1.5 mL solvent with 5 mol% of catalyst (S)-1f at
−15 °C unless otherwise noted. b Isolated yield was listed for entries
3, 4, 5, and 7. c Determined by HPLC analysis (Chiralpak AD-H).
d At −40 °C.
ð2Þ
time. When N-protected 2-methyl indole was used, complete
conversion was achieved yielding product 4aj with 34% ee
(Scheme 2).
To further explore the substrate scope, 1,3,5-trimethoxyben-
zene was also tested under the standard reaction conditions with
2a. The reaction proceeded smoothly to afford the desired product
5 in almost quantitative yield but with only 10% ee (eqn (1)).
ð3Þ
3204 | Org. Biomol. Chem., 2012, 10, 3202–3209
This journal is © The Royal Society of Chemistry 2012

Scheme 2 Substrate scope of 2-formylbiphenyl derivatives.
transformation of 9 to the intermediate II (II′) is added into the
catalytic cycle. The reaction with chiral N-triflyl phosphoramide
might form different type of counterion comparing to chiral
phosphoric acid, which likely contributes the reverse of absolute
configuration of the product. The understanding of the actual
activation mode by different catalysts (N-triflyl phosphoramide
or phosphoric acid) still needs further investigation and might
provide useful guidance in catalyst design.
ð4Þ
ð5Þ
A plausible reaction mechanism was proposed, as depicted in
Scheme 3. Chiral Brønsted acid activates the aldehyde through
the hydrogen bonding with the carbonyl group, enabling the first
Friedel–Crafts reaction between 2a and 3a. The secondary
alcohol I obtained in the presence of chiral Brønsted acid leads
to the formation of a close counterion II or II′, where the anion
creates a chiral environment to control the enantioselectivity over
the second Friedel–Crafts alkylation reaction. Since bisindole 9
can be observed during the reaction and be converted to corre-
sponding product 4aa under the optimized reaction conditions
(51% yield, 81% ee, eqn (6)), a bypass involving the
ð6Þ
Conclusions
In conclusion, chiral N-triflyl phosphoramide was found an
efficient catalyst for the tandem double Friedel–Crafts alkylation
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 3202–3209 | 3205

Scheme 3 Proposed reaction mechanism.
reaction of indoles with 2-formylbiphenyl derivatives. With
biphenyl-2-carbaldehyde 2 (0.10 mmol) was added in one
portion at −15 °C. After the reaction was complete (monitored
by TLC), saturated aqueous NaHCO3 (3 mL) was added to
quench the reaction. The mixture was resumed to room tempera-
ture and extracted with CH2Cl2 (10 mL). The organic layer was
separated and dried over anhydrous Na2SO4. The solvents were
removed under reduced pressure after filtration and the residue
was purified by silica gel column chromatography (ethyl acetate/
petroleum ether = 1/10–1/5) to afford the product.
5 mol% of the optimized catalyst, various fluorene derivatives
were obtained in excellent yields and ee. Notably, the fluorene
products obtained with the chiral N-triflyl phosphoramide have
the opposite absolute configuration compared to that obtained
with the corresponding chiral phosphoric acid. This allows
access to both enantiomers of the products by utilizing different
catalysts derived from one enantiomer of binaphthol.
3-(1,3-Dimethoxy-9H-fluoren-9-yl)-2-methyl-1H-indole (4aa).12
White solid, 92% yield, 90% ee; the enantiomeric ratio was
determined by Daicel Chiralpak AD-H (25 cm), hexanes/IPA =
80/20, 1.0 mL min−1, λ = 254 nm, t (minor) = 7.80 min, t
(major) = 20.91 min; [α]D20 = +15.6° (c = 1.00, acetone); 1H
NMR (400 MHz, DMSO-d6) δ 2.69 (s, 3H), 3.60 (s, 3H), 3.87
(s, 3H), 5.24 (s, 1H), 5.84 (d, J = 8.0 Hz, 1H), 6.38 (d, J = 7.2
Hz, 1H), 6.41–6.42 (m, 1 H), 6.74–6.78 (m, 1H), 7.14 (d, J =
8.0 Hz, 1H), 7.18–7.38 (m, 3 H), 7.34–7.37 (m, 1H), 7.94 (d, J
= 7.6 Hz, 1H), 10.76 (s, 1H).
Experimental
General information
Unless stated otherwise, all reactions were carried out in flame-
dried glassware under a dry argon atmosphere. All solvents were
purified and dried according to standard methods prior to use.
1H and 13C NMR spectra were recorded on a Varian instrument
(300 MHz and 75 MHz, 400 MHz and 100 MHz, respectively)
and internally referenced to tetramethylsilane signal or residual
protio solvent signals. Data for 1H NMR are recorded as follows:
chemical shift (δ, ppm), multiplicity (s = singlet, d = doublet, t =
triplet, m = multiplet or unresolved, br = broad singlet, coupling
constant(s) in Hz, integration). Data for 13C NMR are reported
in terms of chemical shift (δ, ppm). The enantioselectivities
were determined by HPLC analysis and optical rotation was
measured on a polarimeter.
3-(1,3-Dimethoxy-9H-fluoren-9-yl)-2,5-dimethyl-1H-indole
(4ab).12 White solid, 89% yield, 90% ee; the enantiomeric ratio
was determined by Daicel Chiralpak AD-H (25 cm), hexanes/
IPA = 80/20, 1.0 mL min−1, λ = 254 nm, t (minor) = 9.20 min, t
1
(major) = 22.70 min; [α]2D0 = +34.2° (c = 1.0 acetone); H NMR
(400 MHz, DMSO-d6) δ 1.92 (s, 3H), 2.68 (s, 3H), 3.62 (s, 3H),
3.88 (s, 3H), 5.24 (s, 1H), 5.64 (s, 1H), 6.44 (s, 1H), 6.60 (d, J =
7.6 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 7.19–7.23 (m, 3H),
7.37–7.40 (m, 1H), 7.96 (d, J = 7.2 Hz, 1H), 10.62 (s, 1H).
General procedure for the double Friedel–Crafts alkylation
reaction of indoles with 2-formyl biphenyl derivatives
In a dry Schlenk tube, N-triflyl phosphoramide (S)-1f (4.4 mg,
0.005 mmol), substituted indole 3 (0.15 mmol) and 5 Å molecu-
lar sieves (100 mg) were dissolved in o-xylene (1.5 mL) under
argon. The solution was stirred for 5 minutes at room tempera-
ture and then for another 5 minutes at −15 °C. Subsequently,
5-Bromo-3-(1,3-dimethoxy-9H-fluoren-9-yl)-2-methyl-1H-indole
(4ac).12 White solid, 97% yield, 84% ee; the enantiomeric ratio
was determined by Daicel Chiralpak AD-H (25 cm), hexanes/
IPA = 80/20, 1.0 mL min−1, λ = 254 nm, t (minor) = 9.24 min, t
1
(major) = 17.59 min; [α]D20 = +1.8° (c = 1.0 acetone); H NMR
3206 | Org. Biomol. Chem., 2012, 10, 3202–3209
This journal is © The Royal Society of Chemistry 2012

(400 MHz, DMSO-d6) δ 2.68 (s, 3H), 3.61 (s, 3H), 3.87 (s, 3H),
5.24 (s, 1H), 5.88 (d, J = 1.6 Hz, 1H), 6.43 (d, J = 2.0 Hz, 1H),
6.86 (dd, J = 2.0, 8.4 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H),
7.17–7.23 (m, 3H), 7.38–7.40 (m, 1H), 7.97 (d, J = 7.6 Hz, 1H),
11.03 (s, 1H).
10.47 min; [α]2D0 = −20.0° (c = 1.00, acetone); 1H NMR
(300 MHz, CDCl3) δ 3.54 (s, 3H), 3.91 (s, 3H), 5.54 (s, 1H),
6.28 (d, J = 8.4 Hz, 1H), 6.33 (d, J = 1.2 Hz, 1H), 6.58–6.63
(m, 1H), 6.93–6.96 (m, 1H), 7.03 (d, J = 2.1 Hz, 1H), 7.11–7.16
(m, 2H), 7.21–7.23 (m, 1H), 7.29–7.33 (m, 1H), 7.39–7.44 (m,
1H), 7.51–7.55 (m, 2H), 7.77 (d, J = 7.5 Hz, 1H), 7.94–7.97 (m,
3H).
5-Chloro-3-(1,3-dimethoxy-9H-fluoren-9-yl)-2-methyl-1H-indole
(4ad).12 White solid, 97% yield, 85% ee; the enantiomeric ratio
was determined by Daicel Chiralpak AD-H (25 cm), hexanes/
IPA = 80/20, 1.0 mL min−1, λ = 254 nm, t (minor) = 8.91 min, t
(major) = 17.40 min; [α]D20 = +0.52° (c = 1.00, acetone); 1H
NMR (400 MHz, DMSO-d6) δ 2.69 (s, 3H), 3.61 (s, 3H), 3.87
(s, 3H), 5.25 (s, 1H), 5.76 (d, J = 2.0 Hz, 1H), 6.44 (s, 1H), 6.77
(d, J = 8.8 Hz, 1H), 7.15–7.23 (m, 4H), 7.37–7.41 (m, 1H), 7.97
(d, J = 7.2 Hz, 1H), 11.02 (s, 1H).
2-Methyl-3-(1,3,5-trimethoxy-9H-fluoren-9-yl)-1H-indole (4ba).12
White solid, 82% yield, 73% ee; the enantiomeric ratio was
determined by Daicel Chiralpak AD-H (25 cm), hexanes/IPA =
80/20, 1.0 mL min−1, λ = 254 nm, t (minor) = 22.69 min, t
(major) = 41.24 min; [α]D20 = +34.8° (c = 1.00, acetone); 1H
NMR (400 MHz, DMSO-d6) δ 2.36 (s, 3H), 2.63 (s, 3H), 3.57
(s, 3H), 3.85 (s, 3H), 5.18 (s, 1H), 5.84 (d, J = 7.6 Hz, 1H),
6.36–6.40 (m, 2H), 6.74–6.76 (m, 1H), 6.98 (d, J = 7.6 Hz, 1H),
7.04 (d, J = 7.2 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.16 (d, J =
2.0 Hz, 1H), 7.74 (s, 1H), 10.71 (s, 1H).
5-Fluoro-3-(1,3-dimethoxy-9H-fluoren-9-yl)-2-methyl-1H-indole
(4ae).12 White solid, 38% yield, 89% ee; the enantiomeric ratio
was determined by Daicel Chiralpak AD-H (25 cm), hexanes/
IPA = 80/20, 1.0 mL min−1, λ = 254 nm, t (minor) = 8.26 min, t
(major) = 17.29 min; [α]2D0 = −6.0° (c = 1.00, acetone); 1H
NMR (400 MHz, DMSO-d6) δ 2.68 (s, 3H), 3.61 (s, 3H), 3.87
(s, 3H), 5.25 (s, 1H), 5.41–5.44 (m, 1H), 6.43 (d, J = 2.0 Hz,
1H), 6.56–6.21 (m, 1H), 7.12 (dd, J = 4.8, 8.8 Hz, 1H),
7.18–7.22 (m, 3H), 7.36–7.40 (m, 1H), 7.95 (d, J = 7.6 Hz, 1H),
10.89 (s, 1H).
3-(7-Fluoro-1,3-dimethoxy-9H-fluoren-9-yl)-2-methyl-1H-indole
(4ca).12 White solid, 98% yield, 90% ee; the enantiomeric ratio
was determined by Daicel Chiralpak AD-H (25 cm), hexanes/
IPA = 80/20, 1.0 mL min−1, λ = 254 nm, t (minor) = 8.78 min, t
(major) = 17.24 min; [α]D20 = +17.5° (c = 1.00, acetone); 1H
NMR (400 MHz, DMSO-d6) δ 3.20 (s, 3H), 4.07 (s, 3H), 4.33
(s, 3H), 5.75 (s, 1H), 6.47 (d, J = 8.0 Hz, 1H), 6.84 (d, J = 2.0
Hz, 1H), 6.68–6.92 (m, 1H), 7.22–7.26 (m, 1H), 7.39–7.41 (m,
1H), 7.55–7.63 (m, 3H), 8.37 (dd, J = 4.8, 8.0 Hz, 1H), 10.36 (s,
1H).
3-(1,3-Dimethoxy-9H-fluoren-9-yl)-5-methoxy-2-methyl-1H-
indole (4af).12 White solid, 97% yield, 91% ee; the enantio-
meric ratio was determined by Daicel Chiralpak AD-H (25 cm),
hexanes/IPA = 80/20, 1.0 mL min−1, λ = 254 nm, t (minor) =
11.75 min, t (major) = 23.50 min; [α]2D0 = +18.1° (c = 1.00,
3-(7-Chloro-1,3-dimethoxy-9H-fluoren-9-yl)-2-methyl-1H-indole
(4da).12 White solid, 81% yield, 90% ee; the enantiomeric ratio
was determined by Daicel Chiralpak AD-H (25 cm), hexanes/
IPA = 70/30, 0.6 mL min−1, λ = 254 nm, t (minor) = 10.62 min,
1
acetone); H NMR (400 MHz, DMSO-d6) δ 2.64 (s, 3H), 3.24
(s, 3H), 3.60 (s, 3H), 3.86 (s, 3H), 5.23 (s, 1H), 5.26 (s, 1H),
6.39–6.42 (m, 2H), 6.99 (d, J = 8.4 Hz, 1H), 7.19–7.20 (m, 3H),
7.34–7.37 (m, 1H), 7.93 (d, J = 6.8 Hz, 1H), 10.54 (s, 1H).
1
t (major) = 19.11 min; [α]D20 = −32.5° (c = 1.00, acetone); H
NMR (400 MHz, DMSO-d6) δ 2.66 (s, 3H), 3.59 (s, 3H), 3.86
(s, 3H), 5.26 (s, 1H), 5.84 (d, J = 8.0 Hz, 1H), 6.40–6.42 (m,
2H), 6.75–6.78 (m, 1H), 7.13–7.16 (m, 2H), 7.20–7.22 (m, 1H),
7.41 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 10.80 (s, 1H).
7-Bromo-3-(1,3-dimethoxy-9H-fluoren-9-yl)-2-methyl-1H-indole
(4ag).12 White solid, 67% yield, 94% ee; the enantiomeric ratio
was determined by Daicel Chiralpak AD-H (25 cm), hexanes/
IPA = 80/20, 1.0 mL min−1, λ = 254 nm, t (minor) = 9.32 min, t
(major) = 14.67 min; [α]2D0 = −7.8° (c = 1.00, acetone); 1H
NMR (400 MHz, DMSO-d6) δ 2.71 (s, 3H), 3.60 (s, 3H), 3.87
(s, 3H), 5.25 (s, 1H), 5.80 (d, J = 8.0 Hz, 1H), 6.33–6.37 (m,
1H), 6.42 (s, 1H), 6.96 (d, J = 7.6 Hz, 1H), 7.18–7.20 (m, 3H),
7.34–7.36 (m, 1H), 7.93 (d, J = 7.2 Hz, 1H), 10.94 (s, 1H).
3-(6,8-Dimethoxy-9H-fluoreno[3,2-d][1,3]dioxol-9-yl)-2-methyl-
1H-indole (4ea).12 White solid, 79% yield, 87% ee; the enantio-
meric ratio was determined by Daicel Chiralpak AD-H (25 cm),
hexanes/IPA = 80/20, 1.0 mL min−1, λ = 254 nm, t (minor) =
16.79 min, t (major) = 56.69 min; [α]2D0 = −21.1° (c = 1.00,
1
acetone); H NMR (400 MHz, DMSO-d6) δ 2.64 (s, 3H), 3.57
(s, 3H), 3.85 (s, 3H), 5.10 (s, 1H), 5.91 (d, J = 8.0 Hz, 1H),
5.99–6.00 (m, 1H), 6.32 (d, J = 2.0 Hz, 1H), 6.41–6.45 (m, 1H),
6.65 (s, 1H), 6.74–6.78 (m, 1H), 7.11–7.14 (m, 2H), 7.54 (s,
1H), 10.72 (s, 1H).
3-(1,3-Dimethoxy-9H-fluoren-9-yl)-1H-indole (4ah).12 White
solid, 35% yield, 2% ee; the enantiomeric ratio was determined
by Daicel Chiralpak AD-H (25 cm), hexanes/IPA = 80/20,
1.0 mL min−1, λ = 254 nm, t (minor) = 16.11 min, t (major) =
37.90 min; [α]2D0 = −0.4° (c = 1.00, acetone); 1H NMR
(400 MHz, CDCl3) δ 3.60 (s, 3H), 3.92 (s, 3H), 5.37 (s, 1H),
6.37 (s, 1H), 6.87–6.92 (m, 1H), 7.00–7.07 (m, 4H), 7.15–7.20
(m, 1H), 7.24–7.39 (m, 3H), 7.75 (d, J = 10.0 Hz, 1H), 7.89
(s, 1H).
3-(8,10-Dimethoxy-7H-benzo[c]fluoren-7-yl)-2-methyl-1H-indole
(4fa). White solid, 97% yield, 84% ee; the enantiomeric ratio
was determined by Daicel Chiralpak AD-H (25 cm), hexanes/
IPA = 80/20, 1.0 mL min, λ = 254 nm, t (major) = 28.05 min,
t (minor) = 33.29 min; [α]2D0 = +148.1° (c = 0.8, acetone); Mp =
1
203–205 °C; H NMR (300 MHz, CDCl3), δ 2.72 (s, 3H), 3.64
3-(1,3-Dimethoxy-9H-fluoren-9-yl)-2-phenyl-1H-indole (4ai).12
White solid, 8% yield, 28% ee; the enantiomeric ratio was deter-
mined by Daicel Chiralcel OD-H (25 cm), hexanes/IPA = 70/30,
1.0 mL min−1, λ = 254 nm, t (major) = 6.46 min, t (minor) =
(s, 3H), 3.95 (s, 3H), 5.31 (s, 1H), 5.77 (d, J = 7.8 Hz, 1H), 6.29
(t, J = 7.5 Hz, 1H), 6.52 (s, 1H), 6.71 (t, J = 7.5 Hz, 1H), 7.13
(d, J = 8.1 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.57 (t, J = 7.2 Hz,
1H), 7.66 (s, 1H), 7.70–7.78 (m, 2H), 7.99 (d, J = 7.8 Hz, 1H),
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 3202–3209 | 3207

8.87 (d, J = 8.4 Hz, 1H), 10.82 (s, 1H); 13C NMR (75 MHz,
CDCl3) δ 11.7, 43.0, 55.3, 97.0, 100.5, 106.8, 110.2, 117.3,
117.5, 119.3, 123.3, 123.6, 125.1, 126.2, 126.9, 127.3, 128.0,
128.7, 129.1, 133.1, 133.8, 134.1, 135.1, 143.1, 148.3, 156.6,
160.8; IR (thin film): νmax (cm−1) = 3394, 3055, 2921, 2834,
1759, 1596, 1482, 1461, 1426, 1383, 1364, 329, 1305, 1266,
1245, 1214, 1196, 1153, 1132, 1079, 1055, 1016, 936, 817, 786,
766, 738, 661, 620; MS (EI, m/z, rel. intensity) 405 (M+, 100);
HRMS (EI): Exact mass calcd for C28H23NO2: 405.1729,
Found: 405.1726.
(400 MHz, DMSO-d6) δ 2.69 (s, 3H), 3.59 (s, 3H), 3.69 (s, 3H),
3.87 (s, 3H), 5.31 (s, 1H), 5.85 (d, J = 8.0 Hz, 1H), 6.40–6.42
(m, 2H), 6.80–6.84 (m, 1H), 7.16–7.37 (m, 4H), 7.34–7.37 (m,
1H), 7.94 (d, J = 7.6 Hz, 1H).
1,3-Dimethoxy-9-(2,4,6-trimethoxyphenyl)-9H-fluorene
(5).
White solid, 96% yield, 10% ee; the enantiomeric ratio was
determined by Daicel Chiralpak AD-H (25 cm), hexanes/IPA =
80/20, 0.8 mL min, λ = 254 nm, t (major) = 12.73 min, t
1
(minor) = 30.10 min; [α]2D0 = −7.8° (c = 1.0, acetone); H NMR
(300 MHz, DMSO), δ 2.93 (s, 3H), 3.62 (s, 3H), 3.76 (s, 3H),
3.89 (s, 3H), 3.98 (s, 3H), 5.58 (s, 1H), 5.91 (d, J = 2.1 Hz, 1H),
6.28 (d, J = 2.1 Hz, 1H), 6.35 (d, J = 1.8 Hz, 1H), 6.96 (d, J =
2.1 Hz, 1H), 7.17–7.30 (m, 1H), 7.70 (d, J = 7.2 Hz, 1H); 13C
NMR (75 MHz, DMSO) δ 41.3, 55.1, 55.5, 55.7, 56.6, 91.6,
92.7, 96.2, 97.9, 111.2, 119.2, 123.6, 125.9, 126.6, 128.0, 141.2,
143.3, 149.5, 156.6, 159.4, 159.5, 160.2; MS (EI, m/z, rel. inten-
sity) 415 (M + Na); HRMS (EI) calcd for C24H24O5Na (M+):
415.1516, Found: 415.1520.
3-(1,3-Dimethoxy-6-methyl-9H-fluoren-9-yl)-2-methyl-1H-indole
(4ga).12 White solid, 97% yield, 89% ee; the enantiomeric ratio
was determined by Daicel Chiralpak AD-H (25 cm), hexanes/
IPA = 80/20, 1.0 mL min−1, λ = 254 nm, t (minor) = 7.34 min, t
(major) = 17.01 min; [α]D20 = +3.5° (c = 1.00, acetone); 1H NMR
(400 MHz, DMSO-d6) δ 2.38 (s, 3H), 2.65 (s, 3H), 3.54 (s, 3H),
3.85 (s, 3H), 5.18 (s, 1H), 5.85 (d, J = 8.0 Hz, 1H), 6.36–6.40
(m, 2H), 6.71–6.76 (m, 1H), 6.98 (d, J = 7.6 Hz, 1H), 7.04 (d, J
= 7.6 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.16 (d, J = 2.0 Hz,
1H), 7.74 (s, 1H), 10.71 (s, 1H).
3-(9H-1,3-Dioxa-cyclopenta[b]fluoren-9-yl)-2-methyl-1H-indole
(8b). Light yellow solid, 87%, 24% ee; The enantiomeric ratio
was determined by Daicel Chiralpak AD-H (25 cm), hexanes/
IPA = 70/30, 0.5 mL min, λ = 254 nm, t (minor) = 38.21 min,
t (major) = 42.54 min; [α]D20 = +4.7° (c = 1.0, acetone); Mp =
2-Methyl-3-(1,3,6,7-tetramethoxy-9H-fluoren-9-yl)-1H-indole
(4ha). White solid, 89% yield, 92% ee; the enantiomeric ratio
was determined by Daicel Chiralpak AD-H (25 cm), hexanes/
IPA = 80/20, 0.7 mL min, λ = 254 nm, t (minor) = 19.10 min, t
(major) = 26.71 min; [α]2D0 = −19.4° (c = 0.5, acetone); Mp =
1
187–190 °C; H NMR (300 MHz, DMSO), δ 2.73 (s, 3H), 5.24
(s, 1H), 5.88 (d, J = 8.1 Hz, 1H), 6.05 (d, J = 4.2 Hz, 2H), 6.46
(t, J = 7.8 Hz, 1H), 6.75 (s, 1H), 6.82 (t, J = 7.5 Hz, 1H),
7.14–7.22 (m, 3H), 7.36 (t, J = 6.6 Hz, 1H), 7.61 (s, 1H), 7.89
(d, J = 7.8 Hz, 1H); 13C NMR (75 MHz, DMSO) δ 11.5, 44.8,
100.7, 101.1, 105.6, 108.2, 110.3, 117.7, 117.8, 119.1, 119.7,
124.6, 125.8, 125.9, 126.8, 133.8, 134.0, 135.4, 140.5, 142.0,
146.9, 147.1, 148.0; IR (thin film): νmax (cm−1) = 3401, 3059,
2923, 2855, 2770, 2945, 1878, 1708, 1614, 1499, 1473, 1454,
1438, 1339, 1289, 1261, 1230, 1191, 1149, 1100, 1073, 1036,
937, 908, 856, 804, 766, 739, 663, 615; MS (EI, m/z, rel. inten-
sity) 339 (M+, 100); HRMS (EI) calcd for C23H17NO2 (M+):
339.1259, Found: 339.1260.
1
257–259 °C; H NMR (300 MHz, DMSO-d6), δ 2.66 (s, 3H),
3.58 (s, 3H), 3.61 (s, 3H), 3.86 (s, 3H), 3.90 (s, 3H), 5.14 (s,
1H), 5.88 (d, J = 7.8 Hz, 1H), 6.31 (s, 1H), 6.41 (d, J = 7.5 Hz,
1H), 6.72 (s, 1H), 6.75 (t, J = 7.5 Hz, 1H), 7.12 (t, J = 8.1 Hz,
1H), 7.17 (s, 1H), 7.60 (s, 1H), 10.71 (s, 1H); 13C NMR
(75 MHz, DMSO-d6) δ 11.7, 42.5, 55.1, 55.3, 55.5, 55.7, 96.3,
96.7, 103.7, 107.9, 108.2, 110.1, 117.4, 117.7, 119.2, 126.2,
126.3, 133.0, 133.3, 135.1, 141.1, 143.0, 148.4, 148.8, 156.5,
160.7; IR (thin film): νmax (cm−1) = 3388, 3200, 3054, 3000,
2956, 2925, 2854, 2023, 1899, 1866, 1789, 1711, 1601, 1585,
1502, 1462, 1422, 1406, 1362, 1322, 1302, 1265, 1230, 1201,
1185, 1155, 1138, 1091, 1045, 987, 934, 844, 818, 764, 735,
689, 672, 631, 609; MS (EI, m/z, rel. intensity) 415 (M+, 28), 43
(100); HRMS (EI) calcd for C26H25NO4 (M+): 415.1784, Found:
415.1790.
3-[(3′-Methoxy-biphenyl-2-yl)-(2-methyl-3a,7a-dihydro-1H-
indol-3-yl)-methyl]-2-methyl-1H-indole (7a). White solid,
1
99% yield; Mp = 196–198 °C; H NMR (300 MHz, CDCl3), δ
1.87 (s, 6H), 3.31 (s, 3H), 5.84 (s, 1H), 6.39 (s, 1H), 6.76–6.90
(m, 6H), 7.01 (t, J = 7.8 Hz, 2H), 7.13–7.28 (m, 5H), 7.42 (d, J
= 7.8 Hz, 1H), 7.62 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 12.0,
37.2, 54.6, 109.8, 113.4, 119.0, 120.4, 121.0, 126.0, 127.1,
128.5, 129.2, 129.8, 131.7, 135.0, 141.4, 142.2, 143.3, 158.7;
IR (thin film): νmax (cm−1) = 3392, 3055, 2923, 2854, 1929,
1887, 1704, 1594, 1460, 1421, 1340, 1300, 1246, 1217, 1178,
1158, 1095, 1040, 1018, 995, 909, 875, 792, 745, 705; MS (EI,
m/z, rel. intensity) 456 (M+, 100); HRMS (EI) calcd for
C32H28N2O (M+): 456.2203, Found: 456.2202.
2-Methyl-3-(1,3,7-trimethoxy-9H-fluoren-9-yl)-1H-indole (4ia).12
White solid, 98% yield, 92% ee; the enantiomeric ratio was
determined by Daicel Chiralpak AD-H (25 cm), hexanes/IPA =
60/ 40, 0.8 mL min−1, λ = 254 nm, t (minor) = 8.95 min, t
(major) = 29.32 min; [α]D20 = −38.5° (c = 1.00, acetone); 1H
NMR (400 MHz, DMSO-d6) δ 2.66 (s, 3H), 3.57 (s, 3H), 3.66
(s, 3H), 3.85 (s, 3H), 5.19 (s, 1H), 5.89 (d, J = 7.6 Hz, 1H), 6.30
(d, J = 2.0 Hz, 1H), 6.38–6.42 (m, 1H), 6.69 (d, J = 1.6 Hz,
1H), 6.73–6.77 (m, 1H), 6.93 (dd, J = 2.4, 8.4 Hz, 1H), 7.09 (d,
J = 2.4 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.4 Hz,
1H), 10.72 (s, 1H).
3-[(2-Benzo[1,3]dioxol-5-yl-phenyl)-(2-methyl-3a,7a-dihydro-
1H-indol-3-yl)-methyl]-2-methyl-1H-indole (7b). White solid,
1
3-(1,3-Dimethoxy-9H-fluoren-9-yl)-1,2-dimethyl-1H-indole (4aj).12
White solid; 93% yield, 34% ee; the enantiomeric ratio was
determined by Daicel Chiralpak AD-H (25 cm), hexanes/IPA =
80/20, 0.7 mL min−1, λ = 254 nm, t (major) = 8.91 min, t
90% yield; Mp = 252–254 °C; H NMR (300 MHz, CDCl3), δ
1.88 (s, 6H), 5.86–5.88 (m, 3H), 6.49–6.53 (m, 2H), 6.64 (d, J =
8.1 Hz, 1H), 6.80–6.91 (m, 4H), 7.00–7.05 (m, 2H), 7.16–7.26
(m, 5H), 7.40–7.43 (m, 1H), 7.64 (s, 2H); 13C NMR (75 MHz,
CDCl3) δ 12.1, 37.1, 100.7, 107.5, 109.5, 109.8, 113.7, 119.0,
1
(minor) = 25.49 min; [α]2D0 = −3.0° (c = 1.0, acetone); H NMR
3208 | Org. Biomol. Chem., 2012, 10, 3202–3209
This journal is © The Royal Society of Chemistry 2012

J. Wanner, P. Hauwert, H. E. Schoemaker, R. de Gelder, J. H. van Maar-
seveen and H. Hiemstra, Eur. J. Org. Chem., 2008, 180; (g) Q. Kang, X.-
J. Zheng and S.-L. You, Chem.–Eur. J., 2008, 14, 3539; (h) Q. Kang, Z.-
A. Zhao and S.-L. You, Tetrahedron, 2009, 65, 1603; (i) S. Nakamura,
Y. Sakurai, H. Nakashima, N. Shibata and T. Toru, Synlett, 2009, 1639;
( j) F. Xu, D. Huang, C. Han, W. Shen, X. Lin and Y. Wang, J. Org.
Chem., 2010, 75, 8677; (k) M. Rueping, S. Raja and A. Núñez, Adv.
Synth. Catal., 2011, 353, 563; (l) C.-H. Xing, Y.-X. Liao, J. Ng and Q.-
S. Hu, J. Org. Chem., 2011, 76, 4125.
6 (a) M. Terada and K. Sorimachi, J. Am. Chem. Soc., 2007, 129, 292;
(b) Y.-X. Jia, J. Zhong, S.-F. Zhu, C.-M. Zhang and Q.-L. Zhou, Angew.
Chem., Int. Ed., 2007, 46, 5565; (c) G. Li and J. C. Antilla, Org. Lett.,
2009, 11, 1075.
119.3, 120.4, 122.1, 126.0, 127.0, 129.1, 129.9, 130.0, 131.7,
134.9, 141.8, 146.0, 146.7; IR (thin film): νmax (cm−1) = 3378,
2918, 1608, 1556, 1500, 1474, 1459, 1426, 1338, 1303, 1244,
1220, 1125, 1098, 1038, 1014, 930, 894, 861, 821, 766, 746,
641; MS (EI, m/z, rel. intensity) 470 (M+, 100); HRMS (EI)
calcd for C32H26N2O2 (M+): 470.1994, Found: 470.1995.
3,3′-((3′,5′-Dimethoxybiphenyl-2-yl)methylene)bis(2-methyl-
1
1H-indole) (9).12 White solid; H NMR (400 MHz, DMSO-d6)
δ 1.89 (s, 6H), 3.39 (s, 6H), 5.76 (s, 1H), 6.16 (d, J = 2.0 Hz,
2H), 6.34–6.35 (m, 1H), 6.67–6.68 (m, 2H), 6.73 (d, J = 8.0 Hz,
2H), 6.86–6.90 (m, 2H), 7.18–7.20 (m, 3H), 7.23–7.27 (m, 2H),
7.36–7.38 (m, 1H), 10.69 (s, 1H).
7 (a) H.-Y. Tang, A.-D. Lu, Z.-H. Zhou, G.-F. Zhao, L.-N. He and C.-
C. Tang, Eur. J. Org. Chem., 2008, 1406; (b) Q. Cai, Z.-A. Zhao and S.-
L. You, Angew. Chem., Int. Ed., 2009, 48, 7428.
8 (a) J. Itoh, K. Fuchibe and T. Akiyama, Angew. Chem., Int. Ed., 2008,
47, 4016; (b) Y.-F. Sheng, G.-Q. Li, Q. Kang, A.-J. Zhang and S.-L. You,
Chem.–Eur. J., 2009, 15, 3351; (c) Y.-F. Sheng, Q. Gu, A.-J. Zhang and
S.-L. You, J. Org. Chem., 2009, 74, 6899.
Acknowledgements
9 M. Rueping, B. J. Nachtsheim, S. A. Moreth and M. Bolte, Angew.
Chem., Int. Ed., 2008, 47, 593.
10 (a) Q.-X. Guo, Y.-G. Peng, J.-W. Zhang, L. Song, Z. Feng and L.-
Z. Gong, Org. Lett., 2009, 11, 4620; (b) M. Rueping, U. Uria, M.-Y. Lin
and I. Atodiresei, J. Am. Chem. Soc., 2011, 133, 3732.
11 For a double Friedel–Crafts reaction of indole with divinyl ketones: A.
C. Silvanus, S. J. Heffernan, D. J. Liptrot, G. Kociok-Köhn, B.
I. Andrews and D. R. Carbery, Org. Lett., 2009, 11, 1175.
12 F.-L. Sun, M. Zeng, Q. Gu and S.-L. You, Chem.–Eur. J., 2009, 15,
8709.
13 (a) Q. Gu, Z.-Q. Rong, C. Zheng and S.-L. You, J. Am. Chem. Soc.,
2010, 132, 11418; (b) Q. Cai, C. Zheng and S.-L. You, Angew. Chem.,
Int. Ed., 2010, 49, 8666; (c) F.-L. Sun, X.-J. Zheng, Q. Gu, Q.-L. He and
S.-L. You, Eur. J. Org. Chem., 2010, 47; (d) Q. Yin and S.-L. You,
Chem. Sci., 2011, 2, 1344.
We thank the National Basic Research Program of China (973
Program 2009CB825300), National Natural Science Foundation
of China (21025209, 21102160, 21121062) and the Chinese
Academy of Sciences for generous financial support.
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