Diastereoselective friedel-crafts alkylation of indoles with chiral α-phenyl benzylic cations. Asymmetric synthesis of anti-1,1,2- triarylalkanes

Article abstract of DOI:10.1021/ol800858c

(Chemical Equation Presented) The reactions of chiral benzyl carbocations bearing α-phenyl substituents with N-sulfonylated indoles afford 1,1,2-triarylalkanes with antiselectivities. This outcome is a reversal of facial diastereoselectivity relative to B

Full text of DOI:10.1021/ol800858c

ORGANIC
LETTERS
2008
Vol. 10, No. 14
3037-3040
Diastereoselective Friedel-Crafts
Alkylation of Indoles with Chiral
r-Phenyl Benzylic Cations. Asymmetric
Synthesis of Anti-1,1,2-Triarylalkanes
John Y. L. Chung,* Danny Mancheno, Peter G. Dormer, Narayan Variankaval,
Richard G. Ball, and Nancy N. Tsou
Process Research, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey
07065
john_chung@merck.com
Received May 1, 2008
ABSTRACT
The reactions of chiral benzyl carbocations bearing r-phenyl substituents with N-sulfonylated indoles afford 1,1,2-triarylalkanes with anti-
selectivities. This outcome is a reversal of facial diastereoselectivity relative to Bach’s r-alkyl-bearing benzyl cations. The reactions are
promoted by either a Brønsted acid (TFA) or Lewis acid (BF3·OEt2), offering differential diastereoselectivities and reactivities. The electronic
properties of both reacting partners strongly influence the reaction rates and the product diastereoselectivities and appear to operate under
kinetic control. This chemistry provides an efficient access to sterically congested tetrasubstituted ethanes.
Significant efforts have been dedicated to the study of strong
nucleophiles adding to weakly electrophilic chiral R-branched
carbonyl compounds.1 In contrast, the addition of weak
nucleophiles to chiral R-branched strong electrophiles rep-
resents a less studied combination.2 In particular, there are
only a few examples of intramolecular attack on chiral
R-branched benzylic cations.3 Bach et al. have studied the
intermolecular version,4 elegantly demonstrating that arene
nucleophiles add to R-tert-butyl benzyl carbocations to afford
1,1-diaryl-2-tert-butylalkanes 3 in high syn diastereoselec-
tivities (Scheme 1). In connection with a drug development
Scheme 1
.
Friedel-Crafts Alkylation with Chiral R-Branched
Benzyl Cations
(1) (a) Anh, N. T. Top. Curr. Chem. 1980, 88, 145–162. (b) Roush,
W. R. J. Org. Chem. 1991, 56, 4151–4157. (c) Mengel, A.; Reiser, O. Chem.
ReV. 1999, 99, 1191–1223. (d) Takahashi, O.; Yamasaki, K.; Kohno, Y.;
Ueda, K.; Suezawa, H.; Nishio, M. Chem. Asian J. 2006, 1, 852–859.
(2) (a) Mayr, H.; Kuhn, O.; Gotta, M. F.; Patz, M. J. Phys. Org. Chem.
1998, 11, 642–654. (b) Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res.
2003, 36, 66–77.
(3) (a) Lednicer, D.; Emmert, D. E.; Lyster, S. C.; Duncan, G. W. J. Med.
Chem. 1969, 12, 881. (b) Angle, S. R.; Louie, M. S. Tetrahedron Lett.
1989, 30, 5741–5744.
10.1021/ol800858c CCC: $40.75
Published on Web 06/19/2008
2008 American Chemical Society

program, we were interested in applying this reactivity to
R-phenyl benzylic carbocations5 to access 1,1,2-triarylalkanes
6 (Scheme 1).6 Herein, we report the reactions of chiral
benzyl carbocations bearing R-phenyl substituents with arene
nucleophiles, providing efficient access to sterically con-
gested 1,1,2-triarylalkanes 6 in good yields and diastereo-
selectivities. In this chemistry, products were formed wth
predominantly anti-selectivities, representing a reVersal of
the facial diastereoselectivity observed by Bach et al.
(Scheme 1).
A screen of Brønsted/Lewis acids provided viable reaction
conditions for the intermolecular Friedel-Crafts reactions:
(1) 3 equiv of BF3·OEt2/CH2Cl2 (method A); (2) TFA as
solvent (method B). In a first set of experiments, we studied
the reaction of N-benzensulfonyl-indole (14) with benzyl
alcohol 9 as a function of an alkyl R group (Table 1). As
Table 1. Reaction of N-Besyl Indole and R-Phenyl Benzyl
Alcohol 9a-ca
Benzyl alcohols 9 and 13 were prepared by one of two
methods to serve as precursors to the desired benzyl cations
(Scheme 2). Alkylation of desoxybenzoin (7) provided
Scheme 2. Preparation of R-Phenyl Benzyl Alcohols
benzyl
entry alcohol
15:16
R
method anti:synb conversionc yieldd
1
2
3
4
5
6
9a
9a
9b
9b
9c
9c
Me
Me
Et
Et
nPr
nPr
A
B
A
B
A
B
1.7:1
2.8:1
4:1
5.3:1
5.6:1
10:1
93%
90%
90%
95%
94%
95%
82%
80%
85%
80%
80%
84%
a Reaction conditions. Method A: 3 equiv of BF3·OEt2, CH2Cl2 (0.2
M), 22 °C, 20 h. Method B: TFA (0.2 M), 22 °C, 20 h. b The dr of the
product was determined by 1H NMR spectroscopy and HPLC. c HPLC ratios
of (15 + 16)/(14 + 15 + 16). d Yields were determined by HPLC methods
based on isolated products.
the chain length of the R group was increased from methyl
to ethyl and propyl (substrates 9a-c), the anti-selectivity
also increased. Under both sets of conditions, the reactions
proceeded to g90% conversion to afford products 15/16 in
80-85% yields. The TFA conditions afforded better selec-
tivities than the BF3·OEt2 conditions for all three substrates.
The best diastereoselectivity was achieved with n-propyl
substrate 9c, providing a 10:1 ratio of 15c/16c. Identical
product diastereomeric ratios were obtained independent of
the starting material dr’s, implicating a secondary benzylic
cation as a common intermediate in these reactions. The
absolute stereochemical integrity of the R-carbon center was
also maintained during the reaction. We subjected 99% ee
benzyl alcohol 9c to the indole addition reaction and obtained
product 15c in 98% ee.
ketones 8, and subsequent ketone reduction (NaBH4 or
DIBALH) furnished 1,2-diphenylethanol derivatives 9. Al-
ternatively, ketone 10 was subjected to Pd-catalyzed R-ary-
lation7 with para-substituted bromobenzene derivative 11.
Subsequent reduction afforded electronically differentiated
1,2-diarylethanols 13. Alcohols 9 and 13 were mainly of the
anti configuration (dr ) 73/27 to 98/2). Optically active anti-
benzyl alcohols were prepared by asymmetric hydrogenation
reaction via dynamic kinetic resolution (DKR)8 in excellent
enantio- and diastereoselectivities (e.g., 8c to 9c).9,10
(4) (a) Mu¨hlthau, F.; Schuster, O.; Bach, T. J. Am. Chem. Soc. 2005,
127, 9348–9349. (b) Mu¨hlthau, F.; Stadler, D.; Goeppert, A.; Olah, G. A.;
Prakash, G. K. S.; Bach, T. J. Am. Chem. Soc. 2006, 128, 9668–9675. (c)
Stadler, D.; Mu¨hlthau, F.; Rubenbauer, P.; Herdtweck, E.; Bach, T. Synlett
2006, 2573–2576.
The relative stereochemistries of compounds 15 and 16
were assigned anti and syn, respectively, based on 1H NMR
coupling constants and NOE studies (Figure 1).11 In these
(5) Kingsbury, C. A.; Best, D. C. Bull. Chem. Soc. Jpn. 1972, 45, 3440–
3445.
two series of compounds, the observed coupling constants
(6) Stelmach, J. E.; Parmee, E. R.; Tata, J. R.; Rosauer, K. G.; Kim,
R. M.; Bittner, A. R.; Chang, J.; Sinz, C. J. PCT Int. Appl. WO 2008042223,
2008.
3
between the two adjacent methine protons were JHa,b
)
(7) Pd-catalyzed R-arylation of ketones: (a) Palucki, M.; Buchwald, S.
L J. Am. Chem. Soc. 1997, 119, 11108–11109. (b) Kawatsura, M.; Hartwig,
J. F. J. Am. Chem. Soc. 1999, 121, 1473–1478. (c) Fox, J. M.; Huang, X.;
Chieffi, A.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 1360–1370.
(8) (a) Ward, R. S. Tetrahedron 1995, 6, 1475–1490. (b) Ohkuma, T.;
Ooka, H.; Yamakawa, M.; Ikariya, T; Noyori, R. J. Org. Chem. 1996, 61,
4872–4873. (c) Chen, C.-y.; Frey, L. F.; Shultz, S.; Wallace, D. J.;
Marcantonio, K.; Payack, J. F.; Vazquez, E.; Springfield, S. A.; Zhou, G.;
Liu, P.; Kieczykowski, G. R.; Chen, A.; Phenix, B. D.; Singh, U.; Strine,
(9) The absolute stereochemistry of the alcohol was established using
Harada’s MaNP ester method.10 The relative stereochemistry was deter-
mined via NMR coupling constants and NOE studies. See Supporting
Information
.
(10) (a) Nishimura, T.; Taji, H.; Harada, N. Chirality 2004, 16, 13–21.
(b) Kasai, Y.; Sugio, A.; Sekiguchi, S.; Kuwahara, S.; Matsumoto, T.;
Watanabe, M.; Ichikawa, A.; Harada, N. Eur. J. Org. Chem. 2007, 181,
1–1826.
J.; Izzo, B.; Krska, S. W. Org. Process Res. DeV. 2007, 11, 616–623
.
(11) See Supporting Information for additional NOE studies.
3038
Org. Lett., Vol. 10, No. 14, 2008

the R-group from electron-donating (Table 2, entry 2) to
electron-withdrawing (Table 2, entry 8), the product dias-
Table 2. Electronic Effect of Indole Protecting Groupsa
Figure 1. Determination of relative stereochemistries of 15b and
16b via NMR NOE studies.
entry indole
R
method 18:19 anti:synb yieldc
10-11 Hz, indicative of a dihedral angle of ∼180° as the
preferred orientation, as illustrated in the gauche conformers
A and B. On the basis of these conformations, the expected
NOE correlations were observed between the correct sub-
stituents for both the anti and syn diastereomers. In addition,
X-ray analysis of product 24e was performed, corroborating
the NMR stereochemistry assignments (see Supporting
Information).
1
2
3
4
5
6
7
8
17a
17a
14
Tol
Tol
Ph
Ph
A
B
A
B
A
B
A
B
76:24
86:14
85:15
91:9
83:17
89:11
85:15
94:6
74%
73%
80%
84%
93%
60%
94%
92%
14
17b
17b
17c
17c
4-Cl-Ph
4-Cl-Ph
4-NO2-Ph
4-NO2-Ph
The anti-selectivity observed for the nucleophilic addition
to substrates 9a-c is in direct contrast to Bach’s results with
the R-tert-butyl-R-methyl benzyl cation 24 (Scheme 1). On
the basis of A-value consideration, the phenyl group (A )
2.7) is larger than the alkyl groups (Me, A ) 1.7; Et, A )
1.8; nPr, A ) 2.1); however, it behaves as the smaller group
in these substrates. A possible explanation is suggested in
the energy-minimized conformer 5,12 in which the phenyl
group may have a smaller sweep volume than the alkyl group
due to rotational barriers, leading to nucleophilic addition
from that face.13 The behavior of a phenyl group as smaller
than the alkyl group is consistent with the work of Eliel on
1-methyl-1-phenylcyclohexane.14 The data in Table 1 support
this hypothesis, where increasing the length of the alkyl group
increases selectivity.
Arene-arene interactions are speculated to be important
in this mechanistic analysis as well.15 Specifically, the
incoming indole nucleophile could π-π stack with the
phenyl ring of the benzyl cation, as well as support a CH-π
interaction between an indole CH bond (on the five-
membered ring) and the aryl ring oriented ∼90° to the benzyl
cation. Further experiments are required to fully decode the
underlying features of the transition states for these reactions.
Phenonium ion participation is inconsistent with the observed
results because it would lead to syn-products.
a Reaction conditions. Method A: 3 equiv of BF3·OEt2, CH2Cl2 (0.2
M), 22 °C, 20 h. Method B: TFA (0.2 M), 22 °C, 20 h. b The dr of the
product was determined by 1H NMR spectroscopy and HPLC. c Yields were
determined by HPLC methods based on isolated products.
tereoselectivity improved slightly from 86:14 to 94:6. This
improvement in diastereoselectivity coincided with a decrease
in the reaction rates. In general, the TFA conditions afforded
products in higher diastereoselectivities, and the BF3·OEt2
conditions usually proceeded in somewhat faster rates and
better reaction yields.
Next, we studied the electronic effects of a para substituent
in each of the two phenyls in the benzyl alcohol (Table 3).
The electron-donating -OMe substituent in the proximal
X-position dramatically accelerated the reaction rate (Table
3, entry 1). The electron-withdrawing -CN group at this
position completely shut down the Friedel-Crafts reaction,
trifluoroacetylation of the alcohol (22)16 representing the only
product formed (Table 3, entry 3). These trends are consistent
with rate-limiting ionization of the benzyl alcohol. The
presence of an -OMe group in the remote Y-position led to
a slightly slower reaction (entry 4) relative to unsubstituted
substrate 9c. The -CN group at this position gave an
expected significantly slower reaction rate (Table 3, entry
5). Here, the rate vs diastereoselectivity relationship is
opposite of that observed for the study in Table 2, where
the slower-reacting nucleophiles afforded better diastereo-
selectivities.
In a second study, we examined the impact of the
electronic properties of the N-phenylsulfonyl protecting group
on the product diastereoselectivity (Table 2). By changing
To probe the scope and limitation of this chemistry, we
briefly examined other arene nucleophiles: pyrrole, furan,
benzofuran, thiophene, benzothiophene, and 1,3-dimethoxy-
benzene (Table 4). These electron-rich arenes performed
better under BF3·OEt2 conditions to afford moderate yields
of the corresponding products. Benzothiophene and N-nosyl
(12) Molecular modelings were carried out using the Conformer Search
module of CERIUS2. The DREIDING forcefield was used to describe the
energetics. Partial atomic charges were assigned using the charge equilibra-
tion method. See Supporting Information.
(13) Lodge, E. P.; Heathcock, C. H. J. Am. Chem. Soc. 1987, 109, 3353–
3361.
(14) Eliel, E. L.; Manoharan, M. J. Org. Chem. 1981, 46, 1959.
(15) (a) Claessens, C. G.; Stoddart, J. F. J. Phys. Org. Chem. 1997, 10,
254–272. (b) Janiak, C. J. Chem. Soc., Dalton Trans. 2000, 3885–3896.
(c) Takahashi, O.; Kohno, Y.; Iwasaki, S.; Saito, K.; Iwaoka, M.; Tomoda,
S.; Umezawa, Y.; Tsuboyama, S.; Nishio, M. Bull. Chem. Soc. Jpn. 2001,
74, 2421–2430.
(16) Trifluoroacetylation to form 22 retained the stereochemical con-
figuration of the alcohol, implying it formed via esterification and not
ionization suppressed by the dipole-dipole repulsion from the cyano group.
Org. Lett., Vol. 10, No. 14, 2008
3039

Table 3. Electronic Effect of para Substituents on Phenyl
Table 4. Friedel-Crafts Alkylation of Arenes with Chiral
Benzyl Alcohol 9c
Ringsa
benzyl
entry alcohol
20:21
b
X
Y
t1/2
t95
anti:syn yieldc
1
2
3
4
5
13d
9c
13e
13f
13g
MeO
H
CN
H
H
H
H
<5 min 5 min
<5 min 1 h
29:1
15:1
--
20:1
7:1
95%d
92%
0%f
78%
54%
--
--
MeO 5 min
CN 2 h
3 h
H
>20 he
a Reaction conditions: Method B. b Time required to reach 90-95%
conversion. c HPLC yield after 20 h. d Reaction quenched after 1 h. e 76%
conversion after 20 h at rt. f Trifluoroacetylation of the alcohol as the only
product formed (22).
a Reaction conditions. Method A: 3 equiv of BF3·OEt2, CH2Cl2 (0.2
M), 22 °C, 20 h. Method B: TFA (0.2 M), 22 °C, 20 h. b The dr of the
product was determined by 1H NMR spectroscopy and HPLC. c HPLC yield.
d Isolated yield.
pyrrole gave ∼90:10 diastereoselectivity, whereas methylth-
iophene gave a slightly lower 75:25 dr. No selectivity was
observed in the reaction with 1,3-dimethoxybenzene. Reac-
tions involving benzofuran and furan suffered significant
decomposition.
Acknowledgment. We thank R. Reamer and L. DiMichele,
D. Steinhuebel, J. Rosen, C. Bazaral, S. Krska, and R. Ruck,
all of Process Research, Merck Research Laboratories, for
their help and insight.
In summary, the reactions of chiral benzyl carbocations
bearing R-phenyl substituents with N-sulfonylated indoles
afforded 1,1,2-triarylalkanes with anti-selectivities. This
outcome is a reVersal of facial diastereoselectivity relative
to Bach’s R-alkyl-bearing benzyl cations. The reactions are
promoted by either Brønsted acid (TFA) or Lewis acid
(BF3·OEt2), offering differential diastereoselectivities and
reactivities. The reaction rates and product diastereoselec-
tivities are significantly influenced by the electronic proper-
ties of both reacting partners and appear to operate under
kinetic control. Continued efforts will be dedicated to
expanding the scope of weakly nucleophilic partners in this
chemistry.
Supporting Information Available: Representative ex-
perimental procedures, NMR data for all new compounds,
selective HPLC, elemental and mass spec data, modeling
programs and energy-minimized benzylic cation conforma-
tions, and crystallographic information files (CIF) for 24e.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL800858C
3040
Org. Lett., Vol. 10, No. 14, 2008