Chiral α-branched benzylic carbocations: Diastereoselective intermolecular reactions with arene nucleophiles and NMR spectroscopic studies

Article abstract of DOI:10.1021/ja062102g

The chiral benzylic alcohols 1-6 were prepared and subjected to S _N1-type displacement reactions with various arene nucleophiles in acidic medium. Under optimized conditions (HBF₄·OEt ₂, CH₂Cl₂, -78 °

Full text of DOI:10.1021/ja062102g

Published on Web 07/08/2006
Chiral r-Branched Benzylic Carbocations: Diastereoselective
Intermolecular Reactions with Arene Nucleophiles and NMR
Spectroscopic Studies
Friedrich Mu¨hlthau,† Daniel Stadler,† Alain Goeppert,‡ George A. Olah,‡
G. K. Surya Prakash,*,‡ and Thorsten Bach*,†
Contribution from the Lehrstuhl fu¨r Organische Chemie I, Technische UniVersita¨t Mu¨nchen,
D-85747 Garching, Germany, and Loker Hydrocarbon Research Institute and Department of
Chemistry, UniVersity of Southern California, Los Angeles, California 90089-1661
Received March 28, 2006; E-mail: thorsten.bach@ch.tum.de
Abstract: The chiral benzylic alcohols 1-6 were prepared and subjected to SN1-type displacement reactions
with various arene nucleophiles in acidic medium. Under optimized conditions (HBF4‚OEt2, CH2Cl2, -78
°C f r.t.) the corresponding 1,1-diarylalkanes 11-18 and 20 were obtained in good chemical yields (48-
99%). The facial diastereoselectivity of the reaction is high (d.r. ) 91/9-97/3) when the substrate bears a
stereogenic carbon center -CHtBuMe in the R-position to the electrophilic carbon atom. If the starting
material was enantiomerically pure, no significant racemization was observed (94% ee f 92% ee). The
reactions proceed stereoconvergently as demonstrated by the conversion of the separated diastereoisomers
syn-1a and anti-1a in separate reactions to the same product syn-11 (d.r. ) 97/3). Further evidence for
long-lived chiral benzylic carbocations as reaction intermediates was obtained from NMR studies in
superacidic medium. The chiral cation 24 was generated in SO2ClF as the solvent at -70 °C employing
SbF5 as the Lewis acid and characterized by its 1H and 13C NMR spectra. NOE measurements suggest a
preferred conformation in which the diastereotopic faces of the cation are differentiated by the two carbon
substituents R and Me at the stereogenic carbon center in the R-position. The hypothesis is further supported
by the observation that the diastereoselectivity of the substitution reaction decreases if the bulky tert-butyl
(R ) tBu) substituent in the substrate 1a is replaced by a smaller ethyl group (2a, R ) Et).
Introduction
The cationic carbon atom in a trivalent carbocation (carbe-
nium ion) is prostereogenic if its three substituents are different.
In the absence of any chiral information, nucleophilic addition
reactions to free carbenium ions occur stereorandomly, leading
to the known racemization commonly observed in SN1 reac-
tions.1 In this scenario, the plane defined by the three substituents
at the cationic carbon atom exhibits two faces, which are
enantiotopic. If the carbocation is chiral and its cationic carbon
atom center is prostereogenic, the two faces are diastereotopic
(Figure 1). A nucleophilic addition reaction consequently leads
to diastereoisomers which may be formed in nonequal amounts.
In this paper we address the question of facial diastereoselec-
tivity in chiral R-branched benzylic carbocations of the general
structure A. The study includes intermolecular Friedel-Crafts
reactions, in which ions A are generated as intermediates,2 and
NMR experiments, which aimed at structural information on
cations of type A.
Figure 1. Chiral benzylic carbocation of type A and its two diastereotopic
faces defined by the depicted plane (---).
Diastereoselective intramolecular reactions (cyclizations) have
been previously reported in which intermediates of type A are
possibly involved.3 Cyclic 5-substituted 2-methyladamant-2-yl
cations have been studied to elucidate the electronic factors
determining facial selectivity in sterically unbiased substrates.4
(3) (a) Lednicer, D.; Emmert, D. E.; Lyster, S. C.; Duncan, G. W. J. Med.
Chem. 1969, 12, 881-885. (b) Khalaf, A. A.; Roberts, R. M. J. Org. Chem.
1972, 37, 4227-4235. (c) Ziegler, F. E.; Schwartz, J. A. J. Org. Chem.
1978, 43, 985-991. (d) Brown, E.; Loriot, M.; Robin, J.-P. Tetrahedron
Lett. 1979, 20, 1389-1392. (e) Ganeshpure, P. A.; Stevenson, R. J. Chem.
Soc., Perkin Trans. 1 1981, 1681-1684. (f) Taylor, S. K.; Davisson, M.
E.; Hissom, B. R., Jr.; Brown, S. L.; Pristach, H. A.; Schramm, S. B.;
Harvey, S. M. J. Org. Chem. 1987, 52, 425-429. (g) Angle, S. R.; Louie,
M. S. J. Org. Chem. 1991, 56, 2853-2866. (h) Lindstro¨m, U. M.; Somfai,
P. Synthesis 1998, 109-117. (i) Medarde, M.; Ramos, A. C.; Caballero,
E.; Lo´pez, J. L.; Pela´ez-Lamamie´ de Clairac, R.; San Feliciano, A.
Tetrahedron Lett. 1998, 39, 2001-2004. (j) Elings, J. A.; Downing, R. S.;
Sheldon, R. A. Eur. J. Org. Chem. 1999, 837-846. (k) Nagumo, S.;
Miyoshi, I.; Akita, H.; Kawahara, N. Tetrahedron Lett. 2002, 43, 2223-
2228. (l) Mu¨hlthau, F.; Bach, T. Synthesis 2005, 3428-3436.
† Technische Universita¨t Mu¨nchen.
‡ University of Southern California.
(1) For early examples in Friedel-Crafts chemistry, see: (a) Price, C. C.; Lund,
M. J. Am. Chem. Soc. 1940, 62, 3105-3107. (b) Burwell, R. L., Jr.; Archer,
S. J. Am. Chem. Soc. 1942, 64, 1032-1034. (c) Streitwieser, A., Jr.; Stang,
P. J. J. Am. Chem. Soc. 1965, 87, 4953.
(4) (a) Filippi, A.; Trout, N. A.; Brunelle, P.; Adcock, W.; Sorensen, T. S.;
Speranza, M. J. Org. Chem. 2004, 69, 5537-5546. (b) Kaselj, M.; Chung,
W.-S.; le Noble, W. J. Chem. ReV. 1999, 99, 1387-1414. (c) Adcock, W.;
Trout, N. A. Chem. ReV. 1999, 99, 1415-1435.
(2) Preliminary communication: Mu¨hlthau, F.; Schuster, O.; Bach, T. J. Am.
Chem. Soc. 2005, 127, 9348-9349.
9
9668
J. AM. CHEM. SOC. 2006, 128, 9668-9675
10.1021/ja062102g CCC: $33.50 © 2006 American Chemical Society

Chiral
R
-Branched Benzylic Carbocations
A R T I C L E S
Scheme 1
Figure 2. Molecular formula of the secondary and tertiary alcohols 1-6
which served as precursors for the corresponding chiral benzylic carbo-
cations.
In addition, there is a host of information about diastereose-
lective intermolecular reaction of chiral iminium5 and chiral
oxonium6 ions. This issue is further related to the addition of
strong nucleophiles to weak chiral carbonyl electrophiles, such
as ketones and aldehydes, which has been extensively studied.7
Earlier, one of us has investigated the highly enantioselective
addition of indoles to trifluoropyruvates under catalysis by
cinchona alkaloids.8 Despite the synthetic importance acyclic
stereocontrol has gained in organic synthesis,9 it is remarkable
that the intermolecular reaction of weak nucleophiles with
strongly electrophilic carbocations has not been systematically
explored.10 We have started our own investigations with the
chiral alcohols 1-6 (Figure 2), which were used as starting
materials for diastereoselective Friedel-Crafts reactions.11
Treatment of these substrates with various arenes under acidic
conditions should lead to chiral 1,1-arylphenylmethanes.
Previous studies on similar reactions12 had not given a hint
on a possible diastereoselective reaction course.13 However, the
ring opening of a chiral oxazoline under acidic conditions in
o-dichlorobenzene had generated a major diastereomeric ary-
lation product (d.r. ) 93/7), the configuration of which was
not elucidated.14 Some stereoselective cyclizations of biomimetic
type have been carried out under either Lewis or Brønsted acid
catalysis.15
In our studies, the tert-butyl-substituted substrates 1a, 3, 4,
and 5 reacted diastereoselectively with various arene nucleo-
philes. The reaction was shown to be stereoconvergent. The
stereochemical integrity of the R-stereogenic center was evalu-
ated and the product configuration was established. A previously
postulated hypothesis,2 which explains the diastereoselective
reaction course, has now been confirmed by NMR studies on a
chiral carbocation of type A.16 Full details on this work are
provided in the following account.
Results and Discussion
Preparation of Starting Materials. Most of the required
alcohols were synthesized by nucleophilic addition reactions
to a given carbonyl compound. The two starting materials 7
and 8 most commonly used for this purpose are depicted in
Scheme 1. Reduction (NaBH4) or methyl addition (MeMgI) to
ketone 717 furnished the chiral alcohols 1a18 and 1b. The anti-
products were formed as major diastereoisomers due to Felkin-
Anh control.19 Arylmagnesium bromide addition to aldehyde
820 yielded the syn-configurated benzylic alcohols 1a,21 3,22 5,
and 6. The related p-tolyl-substituted alcohol 422 was prepared
in an anti/syn ratio of 65/35 by a Wittig rearrangement. The
ethyl derivatives 2 (R ) Et) were obtained by addition of sec-
butyllithium to benzaldehyde (for 2a) or acetophenone (for 2b).
The simple diastereoselectivity in the addition was expectedly
low. The diastereomeric ratio for 2a23 was 50/50 and for 2b24
60/40.
(5) (a) de Koning, H.; Speckamp, W. N. In Methods of Organic Chemistry,
Vol. E21b; Helmchen, G., Hoffmann, R. W., Mulzer, J., Schaumann, E.,
Eds.; Thieme: Stuttgart, 1996; pp 1953-2010. (b) Schinzer, D. In Organic
Synthesis Highlights II; Waldmann, H., Ed.; VCH: Weinheim, 1995; pp
167-172. (c) Pilli, R. A.; Russowsky, D. Trends Org. Chem. 1997, 6, 101-
123. (d) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56, 3817-
3856. (e) Maryanoff, B. E.; Zhang, H.-C.; Cohen, J. H.; Turchi, I. J.;
Maryanoff, C. A. Chem. ReV. 2004, 104, 1431-1628.
(6) (a) Schmitt, A.; Reissig, H.-U. Synlett 1990, 40-42. (b) Schinzer, D. In
Organic Synthesis Highlights II; Waldmann, H., Ed.; VCH: Weinheim,
1995; pp 173-179. (c) Shaw, J. T.; Woerpel, K. A. Tetrahedron 1999, 55,
8747-8756. (d) Schmitt, A.; Reissig, H.-U. Eur. J. Org. Chem. 2001,
1169-1174. (e) Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.; Smith, D. M.;
Woerpel, K. A. J. Am. Chem. Soc. 2005, 127, 10879-10884 and references
cited therein.
(7) (a) Mengel, A.; Reiser, O. Chem. ReV. 1999, 99, 1191-1223. (b) Devant,
R. M.; Radunz, H.-E. In Methods of Organic Chemistry, Vol. E21b;
Helmchen, G., Hoffmann, R. W., Mulzer, J., Schaumann, E., Eds.;
Thieme: Stuttgart, 1996; pp 1151-1334. (c) Eliel, E. L. In Asymmetric
Synthesis, Vol. 2A; Morrison, J. D., Ed.; Academic Press: Orlando, 1983;
pp 125-155.
(8) To¨ro¨k, B.; Abid, M.; London, G.; Esquibel, J.; To¨ro¨k, M.; Mhadgut, S. C.;
Yan, P.; Prakash, G. K. S. Angew. Chem., Int. Ed. 2005, 44, 3086-3089.
(9) (a) Bartlett, P. A. Tetrahedron 1980, 36, 2-72. (b) Heathcock, C. H. Science
1981, 214, 395-400. (c) No´gra´di, M. StereoselectiVe Synthesis, 2nd ed.;
VCH: Weinheim, 1995.
(10) For diastereoselective addition reactions to a putative allylic cation, see:
Ishikawa, T.; Aikawa, T.; Mori, Y.; Saito, S. Org. Lett. 2004, 6, 1369-
1372.
(11) For recent developments in Friedel-Crafts chemistry, see: (a) Sartori, G.;
Maggi, R. Chem. ReV. 2006, 106, 1077-1104. (b) Sun, Y.; Walsburger,
S.; Tessonier, J.-P.; Louis, B.; Sommer, J. Appl. Catal., A 2006, 300, 1-7.
(c) Choudhury, J.; Podder, S.; Roy, S. J. Am. Chem. Soc. 2005, 127, 6162-
6163. (d) Komoto, I.; Matsuo, J.-I.; Kobayashi, S. Top. Catal. 2002, 19,
43-47. (e) Kawada, A.; Mitamura, S.; Matsuo, J.-i.; Tuschiya, T.;
Kobayashi, S. Bull. Chem. Soc. Jpn. 2000, 73, 2325-2333.
(12) Examples: (a) Hodge, E. B. J. Am. Chem. Soc. 1951, 73, 2341-2342. (b)
Malik, M. S.; Tewari, S. C.; Rastogi, S. N. Ind. J. Chem. 1982, 21B, 919-
922. (c) Alonso, R.; Castedo, L.; Dominguez, D. J. Org. Chem. 1989, 54,
424-428.
(13) For Friedel-Crafts reactions, which proceed stereospecifically, see: (a)
Nakajima, T.; Suga, S.; Sugita, T.; Ichikawa, K. Tetrahedron 1969, 25,
1807-1816. (b) Nakajima, T.; Nakamoto, Y.; Suga, S. Bull. Chem. Soc.
Jpn. 1975, 48, 960-965. (c) Effenberger, F.; Weber, T. Angew. Chem.,
Int. Ed. 1987, 26, 142-143. (d) Piccolo, O.; Azzena, U.; Melloni, G.;
Delogu, G.; Valoti, E. J. Org. Chem. 1991, 56, 183-187. (e) Toshimitsu,
A.; Hirosawa, C.; Tamao, K. Synlett 1996, 465-467. (f) Branchaud, B.
P.; Blanchette, H. S. Tetrahedron Lett. 2002, 43, 351-353. (g) Okamoto,
K.; Nishibayashi, Y.; Uemura, S.; Toshimitsu, A. Tetrahedron Lett. 2004,
45, 6137-6139.
(14) Klumpp, D. A.; Rendy, R.; McElrea, A. Tetrahedron Lett. 2004, 45, 7959-
7961.
(15) Vogel, P. Carbocation Chemistry, Elsevier: Amsterdam, 1985.
(16) Previous studies to resolve stable carbenium ion salts in one of our
laboratories were unsuccessful: Heagy, M. Atropisomerism in Sterically
Hindered Carbocations. Ph.D. Thesis, University of Southern California,
1995.
(17) (a) Chan, T. H.; Paterson, I.; Pinsonnault, J. Tetrahedron Lett. 1977, 4183-
4186. (b) Gansa¨uer, A.; Fielenbach, D.; Stock, C.; Geich-Gimbel, D. AdV.
Synth. Catal. 2003, 345, 1017-1030.
(18) Marcantoni, E.; Alessandrini, S.; Malavolta, M.; Bartoli, G.; Bellucci, M.
C.; Sambri, L.; Dalpozzo, R. J. Org. Chem. 1999, 64, 1986-1992.
(19) (a) Che´rest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 2199-
2204. (b) Anh, N. T.; Eisenstein, O. NouV. J. Chem. 1977, 1, 61-70. (c)
Anh, N. T. Top. Curr. Chem. 1980, 88, 145-162.
(20) Meyers, A. I.; Walkup, R. D. Tetrahedron 1985, 41, 5089-5106.
(21) Arjona, O.; Pe´rez-Ossorio, R.; Pe´rez-Rubalcaba, A.; Quiroga, M. L. J. Chem.
Soc., Perkin Trans. 2 1981, 597-603.
(22) Arjona, O.; Pe´rez-Ossorio, R.; Pe´rez-Rubalcaba, A.; Quiroga, M. L.;
Romero, D. J. Chem. Res., Microf. 1982, 9, 2351-2371.
(23) Al-Aseer, M. A.; Allison, B. D.; Smith, S. G. J. Org. Chem. 1985, 50,
2715-2719.
9
J. AM. CHEM. SOC. VOL. 128, NO. 30, 2006 9669

A R T I C L E S
Scheme 2
Mu¨hlthau et al.
Table 1. Reaction Conditions, Yields, and Diastereoselectivities in
the Friedel-Crafts Alkylation of Furan with Substrate 1a (see
Scheme 3)
furan
temp
C)
timeb
(min)
yieldd
(%)
entry
1aa
acida
(equiv)
(
°
d.r.c
1
2
3
4
5
6
7
anti F3CSO3He
anti F3CSO3He
anti F3CSO3He
anti BF3‚OEt2
anti HBF4‚OEt2
anti HBF4‚OEt2
4
10
4
4
10
4
25
25
0
25
25
15
15
15
75
15
96/4
96/4
97/3
95/5
96/4
97/3
97/3
60
68
63
69
59
94
91
-78 f 25f
-78 f 25f
syn
HBF4‚OEt2
4
a All reaction were conducted at a substrate concentration of 50 mM
and 1.25 equiv of the corresponding Brønsted or Lewis acid was used; anti
refers to anti-1a (d.r. ) 94/6) as starting material and syn to syn-1a (d.r. )
96/4). b Time required for complete conversion. c The diastereomeric ratio
of the crude product was determined by 1H NMR spectroscopy. d Yield of
isolated product. e 0.1 M solution in F2ClCCFCl2. f The acid was added to
1a at -78 °C. After 5 min, furan was added and the mixture was warmed
to room temperature within 15 min.
Compound syn-1a was prepared in enantiomerically pure
form by a conventional resolution (Scheme 2). To this end, the
free racemic alcohol was converted into the corresponding
diastereomeric esters 9 and 10 by treatment with (-)-camphanyl
chloride in pyridine. The diastereoisomers could be separated
by flash column chromatography and their diastereomeric excess
(de) was determined by HPLC. Saponification of the esters
led to the enantiomerically enriched alcohols (+)-syn-1a and
(-)-syn-1a. The separation of the enantiomeric alcohols syn-
1a on various analytical HPLC columns was not feasible. Their
enantiomeric purity (ee) was therefore deduced from the de of
the starting materials under the reasonable assumption that
saponification does not lead to a racemization of both stereo-
genic centers. The specific rotation [R]D of the enantiomers was
Scheme 3
Still, it became evident that side reactions occurred both at
0 °C and at ambient temperature. Yields remained moderate to
good (entries 1-5, 59-68%). With F3CSO3H a significant
decrease of the reaction temperature was impossible, however,
as the solution of F3CSO3H solidified at -35 °C. The handling
of HBF4‚OEt2 at low temperature turned out to be much more
convenient. The reaction could be initiated at -78 °C and went
to completion upon warming to room temperature (entry 6).
This procedure gave superior yields and facilitated the isolation
of clean product simply after workup. The pretreatment of
alcohol 1a with HBF4‚OEt2 and the subsequent addition of the
nucleophile do not necessarily imply a complete carbocation
formation at -78 °C. The protocol allows, however, for the
immediate trapping of any carbocation formed at the lowest
possible temperature (vide infra).
A key issue relevant for further discussion is the observa-
tion that the product distribution did not change upon re-
placing the starting material anti-1a by its diastereoisomer syn-
1a (entry 7, Table 1). In other words, the epimeric composition
anti-1a/syn-1a did not influence the stereoselectivity (stereo-
convergent reaction). A SN2-type displacement can be clearly
ruled out and the result is in line with the intermediacy of a
carbocation of type A.
indeed almost identical in value and opposite in sign ([R]D
)
+45.7 and [R]D ) -45.1, c ) 1, CH2Cl2). The configuration
assignment was based on the specific rotation. The isopropyl
analogues of the tert-butyl compounds syn-1a are known.25 Their
configuration has been established and the specific rotation has
been assigned to either enantiomer. The (1S,2R)-enantiomer was
found to be dextrorotatory ([R]D ) +32.3, c ) 1, CHCl3) and
the (1R,2S)-enantiomer levorotatory ([R]D ) -33.6, c ) 1,
CHCl3).
N-Tosylpyrrole, which was used as one of the arene nucleo-
philes, was prepared from pyrrole by N-tosylation under phase
transfer conditions.26
Intermolecular Reactions with Arene Nucleophiles. Op-
timization experiments for the addition reactions were conducted
with alcohol 1a and with the most sensitive arene nucleophile
employed, i.e., with furan. Some of the results are listed in Table
1 (cf. Scheme 3). In all cases (entries 1-6) a major diastereo-
isomer, syn-11, was formed with high selectivity. The three
depicted acids, F3CSO3H, BF3‚OEt2,27 and HBF4‚OEt2, were
best suited to promote the reaction. The reaction was somewhat
slower in the presence of BF3‚OEt2 (entry 4) as compared to
the two Brønsted acids. The temperature (entries 1 and 3) and
nucleophile concentration (entries 1 and 2) had a minor influence
on the selectivity and yield of the F3CSO3H-catalyzed reaction.
Under optimized conditions (HBF4‚OEt2, CH2Cl2, -78 °C
f r.t.) several other arene nucleophiles were employed in the
reaction of alcohol 1a. The diastereoselectivity was extremely
high in all cases investigated (Figure 3). The diastereomeric
ratio exceeded 94/6 and product yields were satisfactory to
excellent. All arenes (furan, 2-methylthiophene, N-tosylpyrrole,
resorcindimethyl ether, and benzofuran) are comparably nucleo-
philic. The N value for three of the five arenes is tabulated on
Mayr’s scale of nucleophilicity28 with resorcindimethyl ether
(24) Imamoto, T.; Kusumoto, T.; Tawarayama, Y.; Sugiura, Y.; Mita, T.;
Hatanaka, Y.; Yokoyama, M. J. Org. Chem. 1984, 49, 3904-3912.
(25) Cahard, D.; Ferron, L.; Plaquevent, J.-C. Synlett 1999, 960-962.
(26) Anderson, H. J.; Loader, C. E.; Xu, R. X.; Le, N.; Gogan, N. J.; McDonald,
R.; Edwards, L. G. Can. J. Chem. 1985, 63, 896-902.
(27) For a general treatise on Lewis acid catalysis, see: Yamamoto, H., Ed.;
Lewis Acids in Organic Synthesis; Wiley-VCH: Weinheim, 2000.
(28) (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.
9
9670 J. AM. CHEM. SOC. VOL. 128, NO. 30, 2006

Chiral
R
-Branched Benzylic Carbocations
A R T I C L E S
Scheme 4
Figure 3. Structure and yield of the arylation products 12-15 obtained in
diastereoselective reactions of alcohol 1a.
Table 2. Yields and Diastereoselectivities in the Friedel-Crafts
Alkylation of 2-Methylthiophene with Substrates 3-6 (See
Scheme 4)
entrya
substrate
X
product
d.r.b
yieldc (%)
1
2
3
4
3
4
5
6
MeO
Me
Cl
16
17
18
19
91/9
94/6
97/3
-
99
87
91
-
CN
Figure 4. Preferred conformation (according to a crystal structure2) of
compounds syn-11-15 in sawhorse representation (left) and in Newman
projection (right).
a HBF4‚OEt2 was added to the corresponding alcohol 3-6 at -78 °C.
After 5 min, 2-methylthiophene was added and the mixture was warmed to
room temperature within 15 min. b The diastereomeric ratio (d.r.) of the
crude product was determined by 1H NMR spectroscopy. c Yield of isolated
product.
(N ) 2.48) being the most nucleophilic followed by furan (N
) 1.36) and 2-methylthiophene (N ) 1.26). The two arenes
(N-tosylpyrrole, benzofuran) not tabulated should exhibit similar
nucleophilicity (N > 1). Less nucleophilic arenes such as
mesitylene or thiophene (N ) -1.01) failed to undergo a
reaction with 1a. Elimination products were observed, indicating
that the carbocation was formed but not trapped effectively to
avoid the intramolecular side reaction.
Scheme 5
The configuration assignment for compounds 11-15 rests
on an X-ray crystallographic study conducted with single crys-
tals of product 13.2 The synclinal relationship (Figure 4) between
H-1 and H-2, which was established by the crystal structure,
was corroborated for all compounds in solution by a coupling
constant 3JHH = 5.0 Hz. In the major syn diastereoisomers the
hydrogen atom H-1 and the protons at the C-2 methyl group
excellent. The electron-withdrawing cyano group (σpara ) 0.71)29
precluded a reaction presumably because the formation of the
carbocation cannot be promoted by the comparably weak
Brønsted acid HBF4‚OEt2. The minor diastereoselectivity in-
crease that was detected going from X ) MeO to X ) Cl can
be rationalized by the most reactive carbocation (X ) Cl)
reacting at a lower temperature than the more stable carbocations
(X ) Me < X ) MeO). The syn configuration was assigned to
the major products 16-18 obtained in these experiments based
on analogy and based on the NMR data for major and minor
diastereoisomer. As for the major diastereoisomers obtained in
the reaction of 1a, the major products syn-16-18 exhibited a
coupling constant JHH = 5.0 Hz (H-1/H-2) and the H NMR
signals for H-1 and for the methyl group in the major diastereo-
isomer were deshielded relative to the minor diastereoisomer.
The question whether the stereogenic R-carbon atom retains
its stereochemical integrity was addressed by subjecting the
enantiomerically enriched alcohols (+)-syn-1a and (-)-syn-1a
to the reaction conditions of the arylation (Scheme 5). A slight
decrease of enantiomeric excess (94% ee f 92% ee) was
observed for the corresponding product (-)-syn-12 in the
reaction of alcohol (+)-syn-1a. Similar observations were made
for the other enantiomer (-)-syn-1a. The product ee was
determined by chiral HPLC. While the slight ee change may
be associated with uncertainties in the determination of the
substrate ee (vide supra), it became evident that racemization
of starting material is indeed an issue by monitoring the
pretreatment of the alcohol syn-1a with HBF4‚OEt2. The ee
decrease became more significant (<80% ee for product
1
are deshielded by 0.10-0.32 ppm relative to the H NMR
signals of the minor diastereoisomers. The observation is in line
with the crystal structure data, which revealed that the deshield-
ing is likely due to the spatial proximity of the phenyl group
and the relevant hydrogen atoms (H-1, Me). Vice versa, the
configuration assignment for related products can be based on
the 1H NMR chemical shifts provided that the coupling constant
3JHH (H-1/H-2) confirms a preferred synclinal conformation.
Thermodynamic product control was ruled out by subjecting
diastereomeric mixtures of compound 12 (d.r. ) syn/anti )
75/25 to 80/20) to the optimized reaction conditions previously
mentioned (4 equiv of 2-methylthiophene, 1 equiv of HBF4‚OEt2,
CH2Cl2, -78 °C f r.t.). There was no indication for a change
of the d.r. in favor of the major diastereoisomer syn-12. In other
words, while the syn compound syn-12 was formed with excel-
lent diastereoselectivity in the intermolecular Friedel-Crafts
reaction (d.r. ) 95/5), this diastereomeric ratio was not observed
upon attempted thermodynamic equilibration. The diastereo-
meric mixtures with low d.r. (d.r. ) 75/25 to 80/20) had been
isolated from reactions conducted under nonoptimized condi-
tions using other acids and running the reactions at higher tem-
perature [e.g., Yb(OTf)3 at 100 °C]. The results indicate a kinetic
product control in the currently studied Friedel-Crafts reactions.
The influence of a para substituent in the benzyl alcohol
substrate was probed by the reaction of alcohols 3-6 with
2-methylthiophene (Scheme 4, Table 2). With the reaction that
took place (entries 1-3), yields and diastereroselectivities were
3
1
(29) Exner, O. Correlation Analysis of Chemical Data; Plenum Press: New
York, 1988.
9
J. AM. CHEM. SOC. VOL. 128, NO. 30, 2006 9671

A R T I C L E S
Mu¨hlthau et al.
Figure 5. Diastereoselective attack of an arene nucleophile ArH at the
preferred conformation A′ of cation A and structure of product syn-20
obtained by arylation of alcohol 2a.
Scheme 6
Figure 6. 13C NMR spectrum of carbocation 24 (acetone-d6 as external
standard).
were conducted at -70 °C with SbF5 or with FSO3H‚SbF5 in
SO2ClF as the solvent. The secondary carbocations derived from
the alcohols 1a and 2a were not sufficiently stable under these
1
conditions. Decomposition was observed and both H and 13C
NMR spectra were not conclusive. Similarly, the tertiary
carbocation derived from alcohol 1b did not live sufficiently
long enough for meaningful NOE experiments. In this case,
however, the formation of the stable carbocation 21 (Scheme
6) was clearly indicated at low temperature and a peak assign-
ment was possible in the 13C NMR spectrum (see Experimental
Section). In addition, the decomposition process could be
followed by 13C NMR spectroscopy. Both the tert-butyl cation33
and the tertiary benzylic cation 2334 were detected, proving that
a â-elimination is the dominating consecutive reaction. Release
of the tert-butyl cation leads to styrene 22 which upon
protonation provides the observed carbocation 23. The observa-
tion lends support to the earlier mentioned hypothesis that the
reversible â-elimination of a tert-butyl cation is responsible for
the racemization observed in the formation of 1,1-diarylalkane
(-)-syn-12.
Since the â-elimination of the ethyl cation should occur with
a significantly lower rate than the elimination of the tert-butyl
cation, the chances to observe the tertiary cation 24 derived
from alcohol 2b appeared to be good. With SbF5 as the Lewis
acid and SO2ClF as the solvent, clean NMR spectra were
recorded at -70 °C. The 13C NMR spectrum is depicted in
Figure 6. It exhibits 12 carbon signals, the most deshielded
signal being observed at 262.2 ppm relative to acetone-d6 as
the external standard. The aromatic region shows all six carbon
atoms of the phenyl ring. They are magnetically nonequivalent
because the rotation around the phenyl-carbocation bond is
restricted. The 13C NMR chemical shift values for the four
carbon atoms of the sec-butyl group and for the methyl group
are in line with the expected values.
(-)-syn-12) upon prolonging the time for the pretreatment. The
results strongly suggest an addition of the arene nucleophile
immediately after addition of HBF4‚OEt2 if enantiomerically
pure starting materials are employed.
Since we speculated that the racemization occurs by R-depro-
tonation and subsequent reprotonation of the carbocation, we
used the putative intermediate, â-tert-butyl-â-methyl styrene,
as starting material in the Friedel-Crafts reaction. Under
identical conditions no reaction was observed with 2-methyl-
thiophene, which clearly proves that this styrene is not an inter-
mediate in the racemization process. The alternative hypothesis,
namely, that the release of a tert-butyl cation and its subsequent
reaction30 with â-methyl styrene causes the racemization, was
later supported by NMR studies (see Scheme 6).
Carbocation Conformation and NMR Studies. The high
facial diastereoselectivity of the reactions discussed in the
previous chapter has been explained by a kinetic product control
in addition to a chiral carbocation of type A.2 The carbocation
conformation should be determined by 1,3-allylic strain31 and
the preferred conformation should therefore resemble structure
A′ (Figure 5). Attack from a nucleophile ArH at the prostereo-
genic center occurs from the bottom face of the plane defined
by the R-substituent, by the aryl (XC6H4-) substituent, and by
the substituent R1. For the carbocation derived from alcohol
(-)-syn-1a this face is the “re” face. The preferred transition
state for this attack should correlate to the preferred conforma-
tion of the carbocation. According to this model, if the size of
substituent R is reduced, the diastereoselectivty of the arylation
should decrease. Indeed, benzyl alcohol 2a which differs from
1a by the smaller ethyl substituent (R ) Et) at the R-carbon
atom furnished in the reaction with 2-methylthiophene the
corresponding product 20 in a diastereomeric ratio syn/anti )
68/32. The diastereoselectivity for R ) tBu was 95/5.
The 1H NMR spectrum of carbocation 24 was equally well-
resolved and allowed for the projected NOE experiments.
Significant information with regard to its confirmation was
3
expected from the isolated pseudo sextet (3.41 ppm, J = 6.4
Studies were undertaken to elucidate the conformation of
carbocations A by 1H NMR spectroscopy (NOE). Generating a
chiral carbocation under superacidic conditions was attempted,
which in turn should stabilize the short-lived intermediate to
allow for NOE studies at low temperature.32 The experiments
Hz) of the hydrogen atom at the stereogenic center and from
the isolated doublet (0.72 ppm, 3J ) 6.4 Hz) of the methyl group
(32) For reviews, see: (a) Olah, G. A., Prakash, G. K. S., Eds. Carbocation
Chemistry; Wiley: Hoboken, NJ, 2004. (b) Saunders, M.; Jime´nez-Va´zquez,
H. A. Chem. ReV. 1991, 91, 375-397.
(33) Olah, G. A.; Kuhn, S. J.; Tolgyesi, W. S.; Baker, E. B. J. Am. Chem. Soc.
1962, 84, 2733-2740.
(30) The addition of a tert-butyl cation to an olefin is known to be reversible:
Saunders, M.; Lloyd, J. R. J. Am. Chem. Soc. 1977, 99, 7090-7091.
(31) Review: Hoffmann, R. W. Chem. ReV. 1989, 89, 1841-1860.
(34) Olah, G. A.; Spear, R. J.; Forsyth, D. A. J. Am. Chem. Soc. 1977, 99,
2615-2621.
9
9672 J. AM. CHEM. SOC. VOL. 128, NO. 30, 2006

Chiral
R
-Branched Benzylic Carbocations
A R T I C L E S
94%) of product 11, which was obtained as a yellowish oil in a
diastereomeric ratio of syn/anti ) 97/3. In cases in which the product
was not sufficiently pure, a subsequent flash column chromatography
was conducted.
Rf 0.19 (pentane). IR (film): υ˜ 3084 cm-1 (w), 3024 (w), 2960 (s),
1
1803 (m), 1450 (s), 798 (m), 729 (s), 710 (s). H NMR (360 MHz,
CDCl3, 297 K): δ 0.83 (s, 9 H), 0.94 (d, 3J ) 7.2 Hz, 3 H), 1.93 (qd,
3
3
3J ) 7.2 Hz, J ) 4.4 Hz, 1 H), 4.39 (d, J ) 4.4 Hz, 1 H), 6.08 (d,
Figure 7. Major nonvicinal 1H NMR NOE contacts observed in carbocation
24.
3J ) 3.1 Hz, 1 H), 6.30 (dd, J ) 3.1 Hz, J ) 1.5 Hz, 1 H), 7.13-
7.30 (m, 5 H), 7.37 (d, 3J ) 1.5 Hz, 1 H). 13C NMR (90 MHz, CDCl3,
297 K): δ 11.5 (q), 28.2 (q), 34.2 (s), 45.9 (d), 49.5 (d), 107.9 (d),
110.3 (d), 126.0 (d), 128.3 (d), 140.9 (d), 144.6 (s), 156.5 (s), two
aromatic carbon signals are superimposed. MS (EI): m/z (%) 242 (4),
157 (100). Anal. Calcd for C17H22O (242.356): C, 84.25; H, 9.55.
Found: C, 84.20; H, 9.10.
syn-2-(Methyl-5-2,3,3-trimethyl-1-phenylbutyl)thiophene (12). The
compound was prepared from benzylic alcohol 1a (96.2 mg, 500 µmol)
and 2-methylthiophene (196 mg, 2.00 mmol) in CH2Cl2 (10 mL).
Column chromatography (pentane as eluent) yielded 125 mg (459 µmol,
92%) of the desired product 12 as colorless liquid in a diastereomeric
ratio of syn/anti ) 95/5: Rf 0.26 (pentane). IR (film): υ˜ 3058 cm-1
(w), 3022 (w), 2959 (s), 1493 (s), 1449 (s), 794 (m), 698 (s). 1H NMR
3
3
at the same position. The most important NOE connections are
summarized in Figure 7.
Diagnostic NOE contacts were observed between the methyl
group at the cationic carbon atom and an aromatic ortho proton
as well as between the hydrogen atom at the stereogenic center
and an ortho proton. The spatial proximity of these atoms is
perfectly in line with a conformationally restricted intermediate
such as A′ and it is support for the model presented earlier. To
the best of our knowledge, cation 24 is the first acyclic chiral
carbocation, the preferred conformation of which has been
elucidated.
It was not possible to trap the carbocation under the conditions
of stable ion formation with carbon nucleophiles. Side reactions
were predominant. Methyl ether formation was feasible upon
quenching the superacidic solution of cation 24 with methanol.
In line with the preparative Friedel-Crafts experiment leading
to 20, the reaction proceeded with low diastereoselectivity (d.r.
) 60/40). In the latter case, however, a thermodynamic
equilibration cannot be ruled out.
3
(500 MHz, CDCl3, 297 K): δ 0.87 (s, 9 H), 0.99 (d, J ) 7.1 Hz, 3
H), 2.02-2.10 (m, 1 H), 2.43 (s, 3 H), 4.45 (d, J ) 5.0 Hz, 1 H),
6.54-6.59 (m, 1 H), 6.65-6.68 (m, 1 H), 7.17 (t, J ) 7.2 Hz, 1 H),
3
3
7.28 (t, J ) 7.6 Hz, 2 H), 7.35 (d, J ) 7.7 Hz, 2 H). 13C NMR (90
MHz, CDCl3, 297 K): δ 12.7 (q), 15.4 (q), 28.6 (q), 34.6 (s), 48.8 (d),
49.0 (d), 124.4 (d), 125.8 (d), 125.9 (d), 128.2 (d), 128.3 (d), 138.1
(s), 144.5 (s), 146.5 (s). MS (EI): m/z (%) 272 (2), 215 (2), 187 (100).
Anal. Calcd for C18H24S (272.448): C, 79.35; H, 8.88. Found: C, 79.37;
H, 8.90.
3
3
Enantiomerically enriched product (-)-syn-12 (92% ee) was obtained
in a similar fashion from starting material (+)-syn-1a. The enantiomeric
excess (ee) was determined by HPLC (Chiralcel-OJ-H, 250 × 4.6, tR
) 14.7 min; n-hexane/2-propanol ) 70/30, flow rate ) 1 mL/min;
254 nm). [R]D20: +0.2 (c ) 0.89, CH2Cl2). (+)-syn-12 (90% ee) was
Conclusion
In summary, chiral benzylic cations have been shown to be
useful intermediates in SN1 reactions proceeding with acyclic
stereocontrol. Facial diastereoselectivities can be high (d.r. )
>91/9) despite the fact that the chiral electrophile is highly
reactive. The steric outcome of the reactions can be rationalized
by a conformational restriction in the benzylic cation, which
makes the two diastereotopic faces of the prostereogenic cationic
carbon atom distinguishable. Evidence for such a conformational
preference was provided by NMR studies on a stable chiral
benzylic cation under superacidic conditions. The reaction
medium and the nucleophilic strength of the carbon nucleophile
have to be adjusted to comply with the reactivity of the
intermediate and to avoid side reactions. Nonetheless, given the
variety of weak nucleophiles available and given the number
of structural parameters to be altered at a chiral benzylic cation,
there is extensive room for further work in this area. From a
synthetic point of view, the method appears to be extremely
well-suited for the construction of chiral 1,1-diarylalkanes.
obtained from (-)-syn-1a. HPLC: tR ) 11.6 min (Chiralcel-OJ-H, 250
20
× 4.6, n-hexane/2-propanol ) 70/30, flow rate ) 1 mL/min). [R]D
:
-0.7 (c ) 1.23, CH2Cl2).
syn-2-(2,3,3-Trimethyl-1-phenylbutyl)-1-tosyl-1H-pyrrole (13). The
compound was prepared from benzylic alcohol 1a (96.2 mg, 500 µmol)
and tosyl-1H-pyrrole (221 mg, 1.00 mmol) in CH2Cl2 (10 mL). Column
chromatography (pentane/Et2O 90/10 as eluent) yielded 94.0 mg (238
µmol, 48%) of the desired product 13 as white solid in a diastereomeric
ratio of syn/anti ) 94/6: Rf 0.34 (pentane/Et2O 90/10). mp 118 °C. IR
(KBr): υ˜ 3148 cm-1 (w), 2974 (m), 2866 (w), 1491 (s), 1362 (vs),
1
1174 (vs), 1058 (m), 738 (s), 671 (vs). H NMR (360 MHz, CDCl3,
297 K): δ 0.81 (d, 3J ) 7.2 Hz, 3 H), 0.83 (s, 9 H), 1.84-1.94 (m, 1
3
3
H), 2.24 (s, 3 H), 5.02 (d, J ) 5.0 Hz, 1 H), 6.27 (t, J ) 3.5 Hz, 1
H), 6.37-6.41 (m, 1 H), 6.84-6.96 (m, 4 H), 6.99-7.06 (m, 3 H),
7.24 (d, J ) 8.4 Hz, 2 H), 7.34-7.39 (m, 1 H). 13C NMR (90 MHz,
3
CDCl3, 297 K): δ 12.0 (q), 21.6 (q), 28.7 (q), 34.5 (s), 42.4 (d), 51.6
(d), 111.4 (d), 115.2 (d), 122.6 (d), 125.3 (d), 126.8 (d), 127.9 (d),
128.7 (d), 129.4 (d), 136.0 (s), 136.1 (s), 144.1 (s), 144.3 (s); MS (EI):
m/z (%) 395 (2), 310 (100), 154 (23). Anal. Calcd for C24H29NO2S
(395.558): C, 72.87; H, 7.39; N, 3.54; S, 8.11. Found: C, 72.84; H,
7.35; N, 3.39; S, 8.00.
Experimental Section
Representative Procedure for the Diastereoselective Friedel-
Crafts Alkylation. A solution of 96.2 mg (500 µmol) of the alcohol
1a in 10 mL of dry dichloromethane was cooled to -78 °C. After
addition of 102 mg (630 µmol) of HBF4‚OEt2 and stirring of the solution
for 5 min, 136 mg (2.00 mmol) of furan was added and the solution
was warmed to ambient temperature over 15 min. The reaction was
stopped by adding 10 mL of saturated aqueous NaHCO3 after 1 min at
room temperature. The reaction mixture was diluted with 20 mL of
diethyl ether. The organic layer was washed with 10 mL of saturated
aqueous NaHCO3 and with 10 mL of saturated aqueous NaCl. After
drying with NaSO4 concentration in vacuo yielded 114 mg (470 µmol,
syn-1-(1-(2,4-Dimethoxyphenyl)-2,3,3-trimethylbutyl)benzene (14).
The compound was prepared from benzylic alcohol 1a (96.2 mg, 500
µmol) and 1,3-dimethoxybenzene (276 mg, 2.00 mmol) in CH2Cl2 (10
mL). Column chromatography (pentane/Et2O 95/5 as eluent) yielded
145 mg (464 µmol, 93%) of the desired product 14 as colorless oil in
a diastereomeric ratio of syn/anti ) 97/3: Rf 0.30 (pentane/Et2O 95/
5). IR (film): υ˜ 3054 cm-1 (w), 2957 (s), 1611 (s), 1586 (s), 1504 (s),
1292 (s), 1038 (s), 924 (w), 834 (m), 756 (m), 700 (s). 1H NMR (500
3
MHz, CDCl3, 297 K): δ 0.79 (d, J ) 6.9 Hz, 3 H), 0.84 (s, 9 H),
9
J. AM. CHEM. SOC. VOL. 128, NO. 30, 2006 9673

A R T I C L E S
Mu¨hlthau et al.
1
2.32-2.42 (m, 1 H), 3.77 (s, 3 H), 3.81 (s, 3 H), 4.52-4.64 (m, 1 H),
1232 (w), 1091 (s, C-Cl), 1014 (s), 813 (m), 796 (s), 740 (w). H
3
3
6.40-6.46 (m, 2 H), 7.08-7.16 (m, 2 H), 7.23 (t, J ) 7.6 Hz, 2 H),
NMR (360 MHz, CDCl3, 297 K): δ 0.85 (s, 9 H), 0.96 (d, J ) 7.2
7.37 (d, J ) 7.6 Hz, 2 H). 13C NMR (90 MHz, CDCl3, 297 K): δ
Hz, 3 H), 1.99 (qd, 3J ) 7.2 Hz, 3J ) 5.4 Hz, 1 H), 2.42 (s, 3 H), 4.40
(d, 3J ) 5.4 Hz, 1 H), 6.53-6.57 (m, 1 H), 6.64 (d, 3J ) 3.4 Hz, 1 H),
7.20-7.29 (m, 4 H). 13C NMR (90 MHz, CDCl3, 297 K): δ 12.6 (q),
15.3 (q), 28.6 (q), 34.6 (s), 48.3 (d), 49.0 (d), 124.5 (d), 125.9 (d),
128.5 (d), 129.6 (d), 131.7 (s), 138.4 (s), 143.9 (s), 145.0 (s). MS (EI):
m/z (%) 308 (<1), 306 (<1), 223 (36), 221 (100). Anal. Calcd for
C18H23ClS (306.89): C, 70.45; H, 7.55; Cl, 11.55. Found: C, 70.46;
H, 7.49; Cl, 11.64.
3
14.4 (q), 29.0 (q), 34.8 (s), 45.4 (d), 55.3, 55.5, 98.5 (d), 104.2 (d),
125.3 (d), 126.7 (s), 128.1 (d), 128.8 (d), 130.3 (d), 147.5 (s), 157.8
(s), 158.5 (s), one aliphatic signal is superimposed. MS (EI): m/z (%)
312 (2), 255 (2), 227 (100). HRMS (EI) calcd for C21H28O2, 312.2089;
found, 312.2084.
syn-2-(2,3,3-Trimethyl-1-phenyl-butyl)-benzofuran (15). The com-
pound was prepared from benzylic alcohol 1a (96.2 mg, 500 µmol)
and benzofuran (236 mg, 2.00 mmol) in CH2Cl2 (10 mL). Column
chromatography (pentane as eluent) yielded 90.0 mg (308 µmol, 62%)
of the desired product 15 as white solid in a diastereomeric ratio of
syn/anti ) 95/5: Rf 0.10 (pentane). mp 68 °C. IR (KBr): υ˜ 2961 cm-1
(s), 2868 (m), 2359 (w), 1581 (m), 1493 (m), 1454 (s), 1380 (m), 1257
(s), 946 (m), 803 (s), 7411 (vs), 700 (vs). 1H NMR (500 MHz, CDCl3,
297 K): δ 0.91 (s, 9 H), 1.06 (d, 3J ) 7.2 Hz, 3 H), 2.12 (qd, 3J ) 7.2
syn-2-Methyl-5-(2-methyl-1-phenyl-butyl)thiophene (20). The com-
pound was prepared from benzylic alcohol 2a (82.1 mg, 500 µmol)
and 2-methylthiophene (196 mg, 2.00 mmol) in CH2Cl2 (10 mL).
Column chromatography (pentane as eluent) yielded 106 mg (434 µmol,
87%) of the desired product as a colorless oil in a diastereomeric ratio
of syn/anti ) 68/32: Rf 0.26 (pentane). IR (film): υ˜ 3061 cm-1 (w),
3026 (w), 2961 (s), 2919 (m), 2873 (m), 1600 (w), 1494 (m), 1452 (s),
3
3
1
Hz, J ) 4.9 Hz, 1 H), 4.46 (d, J ) 4.9 Hz, 1 H), 6.48 (s, 1 H),
1379 (m), 1032 (w), 793 (m), 740 (m), 700 (vs), 635 (w). H NMR
7.16-7.25 (m, 3 H), 7.30 (t, 3J ) 7.7 Hz, 2 H), 7.38 (d, J ) 7.7 Hz,
3
(360 MHz, CDCl3, 297 K): δ 0.79 (d, 3J ) 6.6 Hz, 0.9 H, [anti]), 0.84
(t, 3J ) 7.3 Hz, 2.1 H, [syn]), 0.91 (t, 3J ) 7.4 Hz, 0.9 H, [anti]), 0.95
(d, 3J ) 6.6 Hz, 2.1 H, [syn]), 0.94-1.06 (m, 0.7 H, [syn]), 1.06-1.19
(m, 0.3 H, [anti]), 1.32-1.46 (m, 0.7 H, [syn]), 1.53-1.66 (m, 0.3 H,
[anti]), 2.03-2.20 (m, 1 H), 2.40 (s, 3 H), 3.71-3.79 (m, 1 H), 6.50-
6.54 (m, 1 H), 6.61-6.67 (m, 1 H), 7.13-7.22 (m, 1 H), 7.23-7.32
(m, 4 H). 13C NMR (90 MHz, CDCl3, 297 K), syn-20: δ 11.3 (q),
15.4 (q), 17.7 (q), 27.5 (t), 40.3 (d), 54.4 (d), 124.0 (d), 124.4 (d),
126.3 (d), 128.2 (d), 128.5 (d), 137.9 (s), 144.4 (s), 146.6 (s). 13C NMR
(90 MHz, CDCl3, 297 K), anti-20: δ 11.4 (q), 15.4 (q), 17.6 (q), 27.8
(t), 40.4 (d), 54.1 (d), 123.9 (d), 124.5 (d), 126.3 (d), 128.3 (d), 128.5
(d), 137.8 (s), 144.4 (s), 146.7 (s). MS (EI): m/z (%) 244 (5), 187
(100). Anal. Calcd for C16H20S (244.39): C, 78.63; H, 8.25. Found:
C, 78.53; H, 8.14.
2 H), 7.45-7.52 (m, 2 H). 13C NMR (90 MHz, CDCl3, 297 K): δ
12.3 (q), 28.4 (q), 34.4 (s), 46.9 (d), 49.1 (d), 104.8 (d), 111.1 (d),
120.5 (d), 122.6 (d), 123.3 (d), 126.3 (d), 128.4 (d), 128.8 (s), 144.0
(s), 154.7 (s), 160.2 (s), one aromatic carbon signal is superimposed.
MS (EI): m/z (%) 292 (4), 208 (23), 207 (100), 178 (39). HRMS (EI)
calcd for C21H24O, 292.1827; found, 292.1828.
syn-2-[1-(4-Methoxy-phenyl)-2,3,3-trimethyl-butyl]-5-methylthio-
phene (16). The compound was prepared from benzylic alcohol 3 (111
mg, 500 µmol) and 2-methylthiophene (196 mg, 2.00 mmol) in
CH2Cl2 (10 mL). Column chromatography (pentane as eluent) yielded
150 mg (496 µmol, 99%) of the desired product as a colorless oil in a
diastereomeric ratio of syn/anti ) 91/9: Rf 0.08 (pentane). IR (film):
υ˜ 2958 cm-1 (s), 1609 (m), 1583 (w), 1510 (vs), 1463 (m), 1301 (w),
1
1247 (vs), 1179 (s), 1047 (s), 822 (m), 797 (s). H NMR (360 MHz,
NMR Studies. 2-Phenyl-3,4,4-trimethyl-pentane-2-carbeniumion
(21). The benzylic alcohol 1b (22.0 mg, 106 µmol) was mixed with
SO2ClF at -78 °C in a NMR tube. A solution of SbF5 in SO2ClF
precooled to -78 °C was added and the deep green solution was
properly mixed. After addition of the precooled external standard
acetone-d6 the mixture was inserted into the NMR, which was already
cooled to -90 °C. 13C NMR (100 MHz, SO2ClF, external standard
CDCl3, 297 K): δ 0.86 (s, 9 H), 0.96 (d, 3J ) 7.2 Hz, 3 H), 2.00 (qd,
3
3J ) 7.2 Hz, J ) 5.3 Hz, 1 H), 2.41 (s, 3 H), 3.77 (s, 3 H), 4.38 (d,
3
3J ) 5.3 Hz, 1 H), 6.52-6.56 (m, 1 H), 6.63 (d, J ) 3.4 Hz, 1 H),
3
3
6.81 (d, J ) 8.7 Hz, 2 H), 7.24 (d, J ) 8.7 Hz, 2 H). 13C NMR (90
MHz, CDCl3, 297 K): δ 12.7 (q), 15.4 (q), 28.6 (q), 34.6 (s), 48.0 (d),
49.1 (d), 55.3 (q), 113.7 (d), 124.4 (d), 125.6 (d), 129.1 (d), 138.0 (s),
138.8 (s), 145.0 (s), 157.8 (s). MS (EI): m/z (%) 302 (<1), 245 (2),
217 (100). Anal. Calcd for C19H26OS (302.47): C, 75.45; H, 8.66; S,
10.60. Found: C, 75.40; H, 8.45; S, 10.64.
1
1
acetone-d6, 183 K): δ 13.8 (q, JC-H ) 130.0 Hz), 27.4 (q, JC-H
)
125.4 Hz), 28.9 (q, 1JC-H ) 144.1 Hz), 42.2 (s), 58.2 (d, 1JC-H ) 133.0
Hz), 131.1 (d, 1JC-H ) 173.3 Hz), 131.7 (d, 1JC-H ) 174.0 Hz), 138.9
1
1
(d, JC-H ) 165.5 Hz), 139.2 (d, JC-H ) 167.9 Hz), 141.1 (s), 154.0
syn-2-Methyl-5-(2,3,3-trimethyl-1-p-tolyl-butyl)thiophene (17). The
compound was prepared from benzylic alcohol 4 (103 mg, 500 µmol)
and 2-methylthiophene (196 mg, 2.00 mmol) in CH2Cl2 (10 mL).
Column chromatography (pentane as eluent) yielded 124 mg (433 µmol,
87%) of the desired product as a colorless oil in a diastereomeric ratio
of syn/anti ) 94/6: Rf 0.31 (pentane). IR (film): υ˜ 3047 cm-1 (w),
2960 (s), 1512 (vs), 1479 (s), 1469 (s), 1396 (m), 1378 (s), 1364 (s),
1233 (m), 1118 (w), 1034 (m), 796 (vs), 728 (w). 1H NMR (500 MHz,
CDCl3, 297 K): δ 0.86 (s, 9 H), 0.98 (d, 3J ) 7.2 Hz, 3 H), 2.03 (qd,
1
(d, JC-H ) 169.1 Hz), 262.7 (s).
3-Methyl-2-phenyl-pentane-2-carbeniumion (24). The benzylic al-
cohol 2b (30.0 mg, 168 µmol) was added to SO2ClF at -78 °C in a
test tube and mixed to yield a homogeneous solution. The solution of
the alcohol was added quickly at -78 °C to an analogously prepared
solution of SbF5 in SO2ClF. The deep red mixture was transferred to
a NMR tube at -78 °C and a precooled external acetone-d6 standard
was inserted. The sample was than transferred into the precooled NMR
(-70 °C). 1H NMR (400 MHz, SO2ClF, external standard acetone-d6,
3
3J ) 7.2 Hz, J ) 5.3 Hz, 1 H), 2.31 (s, 3 H), 2.42 (s, 3 H), 4.41 (d,
3
3J ) 5.3 Hz, 1 H), 6.53-6.58 (m, 1 H), 6.64 (d, J ) 3.3 Hz, 1 H),
3
3
203 K): δ 0.20 (t, J ) 7.6 Hz, 3 H), 0.72 (d, J ) 6.4 Hz, 3 H),
1.00-1.26 (m, 2 H), 2.55 (s, 3 H), 3.41 (virt sext, J = 6.4 Hz, 1 H),
3
3
7.09 (d, J ) 8.0 Hz, 2 H), 7.23 (d, J ) 8.0 Hz, 2 H). 13C NMR (90
MHz, CDCl3, 297 K): δ 12.7 (q), 15.4 (q), 21.1 (q), 28.7 (q), 34.6 (s),
48.4 (d), 49.0 (d) 124.4 (d), 125.7 (d), 128.1 (d), 129.0 (d), 135.4 (s),
138.0 (s), 143.6 (s), 144.9 (s). MS (EI): m/z (%) 286 (1), 229 (2), 201
(100). Anal. Calcd for C19H26S (286.47): C, 79.66; H, 9.15. Found:
C, 79.68; H, 9.02.
3
3
3
7.10 (virt q, J = 7.7 Hz, 2 H), 7.69 (t, J ) 7.1 Hz, 1 H), 7.91 (virt
t, J = 9.8 Hz, 2 H). 13C NMR (100 MHz, SO2ClF, external standard
3
1
1
acetone-d6, 203 K): δ 11.5 (q, JC-H ) 128.5 Hz), 19.2 (q, JC-H
)
1
1
131.1 Hz), 26.2 (q, JC-H ) 131.6 Hz), 32.1 (t, JC-H ) 131.5 Hz),
50.4 (d, 1JC-H ) 135.8 Hz), 131.8 (dd, 1JC-H ) 170.0 Hz, 2JC-H ) 7.0
Hz), 132.0 (dd, 1JC-H ) 171.5 Hz, 2JC-H ) 6.8 Hz), 139.1 (d, 1JC-H
)
)
syn-2-[1-(4-Chlorophenyl)-2,3,3-trimethyl-butyl]-5-methylthio-
phene (18). The compound was prepared from benzylic alcohol 5 (113
mg, 500 µmol) and 2-methylthiophene (196 mg, 2.00 mmol) in
CH2Cl2 (10 mL). Column chromatography (pentane as eluent) yielded
139 mg (453 µmol, 91%) of the desired product as a colorless oil in a
diastereomeric ratio of syn/anti ) 94/6: Rf 0.36 (pentane). IR (film):
υ˜ 3060 cm-1 (w), 2961 (vs), 2867 (m), 1490 (vs), 1396 (m), 1365 (m),
1
1
166.7 Hz), 139.3 (s), 140.8 (d, JC-H ) 167.3 Hz), 154.7 (d, JC-H
166.1 Hz), 262.2 (s).
Acknowledgment. This work was supported by the Fonds
der Chemischen Industrie (Frankfurt/Main) in Germany. Work
in the U.S.A. was supported by the Loker Hydrocarbon Research
9
9674 J. AM. CHEM. SOC. VOL. 128, NO. 30, 2006

Chiral
R
-Branched Benzylic Carbocations
A R T I C L E S
Institute and by the Stauffer Foundation. This paper is dedicated
to Professor David A. Evans (Harvard University) on the
occasion of his 65th birthday.
13C NMR data for the known starting materials syn-1a, anti-
1a, 2a, 2b, 3, and 4. 13C NMR spectra of all compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org. See any current masthead page for ordering
information and Web access instructions.
Supporting Information Available: Complete analytical data
for the yet unreported starting materials (+)-syn-1a, (-)-syn-
1
1a, 1b, 5, and 6 and procedures for their preparation. H and
JA062102G
9
J. AM. CHEM. SOC. VOL. 128, NO. 30, 2006 9675