Asymmetric synthesis of diverse α,α-diarylmethylamines via aryl Grignard additions to chiral N-2,4,6-triisopropylbenzenesulfinylimines

Article abstract of DOI:10.1016/j.tet.2011.07.019

A mild method has been developed for the asymmetric synthesis of a variety of chiral diarylmethylamines via the addition of aryl Grignard reagents to chiral N-2,4,6-triisopropylbenzenesulfinylimines in high yields and high diastereoselectivities. Higher s

Full text of DOI:10.1016/j.tet.2011.07.019

Tetrahedron 67 (2011) 7035e7041
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Asymmetric synthesis of diverse a,a-diarylmethylamines via aryl Grignard
additions to chiral N-2,4,6-triisopropylbenzenesulfinylimines
*
Zhengxu Han , Robert Busch, Keith R. Fandrick, Angelica Meyer, Yibo Xu, Dhileep K. Krishnamurthy,
Chris H. Senanayake
Department of Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 May 2011
Received in revised form 6 July 2011
Accepted 7 July 2011
Available online 18 July 2011
A mild method has been developed for the asymmetric synthesis of a variety of chiral diarylmethyl-
amines via the addition of aryl Grignard reagents to chiral N-2,4,6-triisopropylbenzenesulfinylimines in
high yields and high diastereoselectivities. Higher stereoselectivity was obtained for most of the ex-
amples studied when the reactions are performed at ambient temperature as compared to cryogenic
conditions. N-2,4,6-Triisopropylbenzenesulfinamide was shown to be the optimal chiral auxiliary as it
provided higher diastereoselectivities when compared to the more commonly employed tert-butane-
sulfinamide or p-toluenesulfinamide in the synthesis of diarylmethylamine synthons. A rationale for the
improved selectivity derived from the triisopropylbenzyl auxiliary is presented.
Keywords:
Chiral sulfinamide
Sulfinylimine
Chiral diarylmethylamines
Asymmetric synthesis
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
The organometallic addition to chiral sulfinylimines would
provide a direct and practical approach to chiral diarylmethyl-
a
,
a
-Diarylmethylamines 1 (Fig. 1) are components of many
amines. We are interested in employing this chemistry in the
synthesis of diarylmethylamines 2 that contain strong electron
donating group. The synthesis of 2 via organometallic addition to
tert-butanesulfinylarylaldimine was reported but the reaction was
void of stereoselectivity.4a Additionally, few reports have studied
the relationship between the structure of the chiral sulfinamides
and the stereoselectivity of the corresponding organometallic ad-
dition. Recently, in the process development for the synthesis of
(S)-cetirizene, we identified a hindered arenesulfinamide, 2,4,6-
triisopropylbenzenesulfinamide (TIPPSA, 3c) as the optimal chiral
auxiliary in the synthesis of the key intermediate (S)-(4-
chlorophenyl)phenylmethaneamine.14,15 It was observed that the
phenyl magnesium bromide addition to an aldimine derived from
pharmaceutical and bioactive molecules.1aef,12 In the last decade,
efforts have been devoted toward developing practical syntheses of
these important synthons.2e9 Methods for the synthesis of 1 via
stereoselective addition of organometallic reagents to a suitable
chiral imine species are reported including the catalytic asym-
metric additions of arylboronic acids, aryl boroxines, or aryl tita-
nium reagents to N-arylsulfonylimines, arylboronic acids to N-Boc
imines,8e11 phenylzinc reagents to masked N-formylimine,12 and
arylboronic acids5,6,13 to chiral N-tert-butanesulfinyl or N-diphe-
nylphosphinoyl imines with good to excellent stereoselectivity.
However, few reports have addressed the asymmetric additions of
aryl organometallic reagents to chiral sulfinylimines.3,4
O
S
O
S
NH2
NH2
O
S
NH2
NH2
NH2
R1
R2
R
NMe2
2
1
3a
3b
3c
Fig. 1. Stuctures of diaryl methamines 1 and 2 and chiral benzenesulfinamides 3aec.
3c afforded the product in higher stereoselectivity than either t-
BSA (3a) or p-TSA (3b). Herein we wish to report a detailed study on
the application of TIPPSA in the synthesis of 2 with diverse func-
tionalities under mild reaction conditions.
* Corresponding author. Tel.: þ1 203 798 4769; fax: þ1 203 791 6130; e-mail
address: shan@rdg.boehringer-ingelheim.com (Z. Han).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.07.019

7036
Z. Han et al. / Tetrahedron 67 (2011) 7035e7041
2. Results and discussions
The reactions were first performed at ꢀ40 ꢁC by the addition of
2 equiv of readily available Grignard 6 to an aldimine solution in
toluene15c under an inert atmosphere (Table 1). The reactivity of the
sulfinimines was similar, but the selectivity was proportional to the
size of the substituent on the sulfinylimine. Using t-BSA as the
auxiliary, the addition reaction was complete in about 30 min
providing the desired product 7aa in excellent yield and moderate
selectivity (70% de). Reactions of the tolyl sulfinylimine 5ba with 6
afforded the addition product in poor selectivity (16% de). However
with TIPPSA as the auxiliary, the reaction was complete in 1 h and
afforded the product 7ca in good yield and 82% de.
Chiral tert-butanesulfinamide (t-BSA) has been widely utilized
as a chiral auxiliary in the synthesis of chiral amines through the
addition of suitable nucleophiles to the corresponding chiral sul-
finylimines.16 Most notably, the bulky tert-butyl group of 3a has
been shown to offer improved facial discrimination because the
bulky tert-butyl group maintains the desired conformation in the
transition state for the nucleophilic addition.20 However, studies
have shown that in some cases the reactivity of the sulfinylimines
was diminished due to the large size of tert-butyl moiety.17 Recent
Table 1
Results on the addition of 6 to aldimines 5aa, 5ba, and 5ca
O
MgBr
S
O
S
O
S
R
HN
R
NH2
N
R
Me2N
toluene
CHO
6
3a-c
NMe2
Ti(OEt)4/THF
7
5
4a
Imines
Products
Reaction temperature
5
7
ꢀ40 ꢁC
rt
O
S
O
S
85:15 dra
84:16 dr
99% conversion
10 min
HN
N
90% conversionb
30 min
5aa
NMe2
7aa
O
S
O
S
58:42 dr
88% conversion
1 h
65:35 dr
95% conversion
20 min
HN
N
7ba
5ba
NMe2
iPr
O
S
O
iPr
S
N
91:9 dr
95% conversion
1 h
91:9 dr
99% conversion
10 min
HN
iPr
iPr
NMe2
iPr
iPr
7ca
5ca
a
Diastereomeric ratio (dr) based on 1H NMR analysis of the benzylic proton and/or secondary amine proton of the crude product.
b
Conversion is based on 1H NMR analysis and verified by the isolated yields, which closely correlate with the reported conversions.
reports have demonstrated that the use of 2,4,6-
Due to the improved selectivity for the addition reactions with the
TIPPSA as the chiral auxiliary, the synthesis of a variety of (4-N,N-
dimethylaminophenyl)arylmethaneamines was studied. The re-
actions were first performed at ꢀ40 ꢁC and it was observed that the
electrophile had a noticeable effect on the reactivity and selectivity of
the addition reactions. As mentioned above, that reaction of 6 with
5ca at ꢀ40 ꢁC proceeded to completion in about 1 h and provided the
addition product 7ca (91:9 dr). The corresponding additions of 6 to
sulfinylimine 5cb, 5cc, and 5cd, which contain the electron with-
drawing chloride, fluoride, and trifluoromethyl functionality, re-
spectively, was complete in less than 30 min and provided the
additionproducts7cb, 7cc, and 7cd withdrs of 86:14, 86:14, and 91:9,
respectively. However, the reaction rate decreased dramatically for
the reaction with p-methoxyphenyl sulfinylimine 5ce in which only
83% conversion was observed after 20 h and afforded 7ce (94:6 dr).
The temperature effect on the addition reactions was also in-
vestigated. Typically, lower reaction temperatures correspond to an
increase in the stereoselectivity in a given asymmetric process. In-
terestingly, for the electron deficient aldimines an increase in
triisopropylbenzenesulfinamde (TIPPSA) overcame this limitation
in the asymmetric process.17e19 Since our first report on the syn-
thesis of enantiopure TIPPSA,3a several reports have demonstrated
that this chiral auxiliary not only allowed for retained reactivity but
also provided the steric hindrance necessary for high stereo-
selectivity.17e19 Therefore, the scope of the application of TIPPSA for
the synthesis of diarylmethylamines with various functionalities
was studied.
The effect of chiral sulfinamides on stereoselectivity was first
studied in the synthesis of (4-N,N-dimethylaminophenyl)phenyl-
methaneamine 2a. Recently, Plobeck and Powell4a studied the or-
ganometallic addition to the aldimine (5aa) derived from
benzaldehyde and t-BSA and observed no reaction when the cor-
responding 4-(dimethylamino)phenyl magnesium bromide (6) was
used. Therefore, our initial studies focused on the addition of 6 to
aldimines 5aa, 5ba, and 5ca that were prepared in excellent yield
by the condensation of benzaldehyde with t-BSA, p-TSA, and TIPPSA
in the presence of Ti(OEt)4, respectively (Fig. 1).3

Z. Han et al. / Tetrahedron 67 (2011) 7035e7041
7037
stereoselectivity was observed when the reactions were performed
at ambient temperature as compared to ꢀ40 ꢁC (Table 2). It should
also be noted that with the electron donating p-methoxy aldimine
5ce only a slight decrease in stereoselectivity was observed with the
40 ꢁC increase in reaction temperature (ꢀ40 ꢁC 88% de; rt 84% de).
only 1.5 h. Similar results were observed using p-methoxylphenyl
magnesium bromide. It was observed that, in most cases, the ad-
dition reaction to aryl sulfinylimines 5cc or 5cd that contain
a strong electron withdrawing substituent is relatively faster and
the stereoselectivity is moderate to good (72e88% de). Remarkably,
Table 2
Effects of temperature on the addition of Grignard reagent 6 to aldimines 5cbece
O
O
iPr
iPr
MgBr
S
S
N
HN
iPr
iPr
iPr
Me2N
6
TIPP
iPr
toluene
R
R
NMe2
5
7
Imines
Products
Reaction temperature
5
7
ꢀ40 ꢁC
rt
O
S
O
S
TIPP
TIPP
TIPP
91:9 dra
93:7 dr
99% conversion
10 min
HN
TIPP
N
99% conversionb
45 min
5cb
Cl
NMe2
NMe2
NMe2
7cb
Cl
O
S
O
S
86:14dr
99% conversion
30 min
91:9 dr
99% conversion
10 min
HN
N
TIPP
5cc
F
7cc
F
O
S
O
S
86:14 dr
99% conversion
30 min
>95:5 dr
99% conversion
10 min
HN
N
TIPP
TIPP
F3C
F3C
7cd
5cd
O
O
S
S
TIPP
94:6 dr
92:8 dr
99% conversion
10 min
N
HN
83% conversion
20 hc
7ce
5ce
MeO
MeO
NMe2
a
Diastereomeric ratio (dr) based on 1H NMR analysis of the benzylic proton and/or secondary amine proton of the crude product. The 95:5 ratio indicates that the other
diastereomer was not detected.
b
Conversion is based on 1H NMR analysis and verified by the isolated yields, which closely correlate to the reported conversions.
The reaction was first conducted at ꢀ40 ꢁC for about 4e6 h and then warmed slowly to rt and stirred for 15 h.
c
The scope of the TIPPSA chemistry was extended to the syn-
thesis of a variety of diarylmethylamines with different aryl sub-
stituents. The addition reactions of Grignard reagents 7e9 to
imines 5caece were first performed at ꢀ40 ꢁC where the reaction
time, conversion, and stereoselectivity were monitored (Table 3). It
was observed that the nucleophilicity or electrophilicity of the re-
action partners had a noticeable effect on the conversion. Slow
reactions were observed for the addition of phenyl magnesium
bromide 7 to 5cb and 5ce where the reaction was complete in 20 h.
In contrast the reactions of 7 with 5ccꢀor 5cd, which contained
strong electron withdrawing Fꢀ and CF3 groups was complete in
the reaction of p-chlorophenyl magnesium bromide 9 with phenyl
aldimine 5cc was complete in 20 h but took 2 h with p-tri-
fluoromethylphenyl aldimine 5cd providing the desired product
12cc and 12cd in 82% de. This example highlights the impact of the
substituent on the reactivity of the aldimines.
In order to make the asymmetric synthesis of the diarylmethyl-
amines more practical, the corresponding organometallic additions
were conducted at ambient temperatures (Table 3). A significant
effect was observed for all of the reactions explored. First, the re-
action ratewas increased with complete conversions being obtained
in 20e60 min. In the majority of examples surveyed we observed an

7038
Z. Han et al. / Tetrahedron 67 (2011) 7035e7041
Table 3
Addition of Grignard reagents 7e9 to aldimines 5caece at ꢀ40 ꢁC and rt in toluene for the synthesis of 10e12
O
S
NH2
S
S
N
TIPP
HN
Ar1
Ar2MgBr (7-9)
O
3c
O
Ar1CHO
Ar1
toluene
Ar2
10-12
Ti(OEt)4/THF
5ca-ce
Imines 5
Grignard
Reaction temperature
MgBr
MgBr
MgBr
7
MeO
Cl
9
8
O
S
O
S
O
HN TIPP
HN TIPP
S
ꢀ40 ꢁC
N
TIPP
Cl
rt
OMe
12ca
11ca
20 h,c 93:7,b 62%a
20 min, 94:6, 99%
20 h, 85:15, 90%
1 h, >95:5, 98%
5ca
O
O
S
S
O
S
HN TIPP
HN TIPP
N
TIPP
ꢀ40 ꢁC
Cl
rt
OMe
Cl
10cb
11cb
Cl
20 h, 88:12, 65%
20 min, 92:8, 99%
5cb
20 h, 91:9, 86%
20 min, 93:7, 99%
O
O
O
S
S
S
O
S
HN TIPP
HN TIPP
HN TIPP
N
TIPP
ꢀ40 ꢁC
Cl
F
F
OMe
rt
F
10cc
12cc
11cc
F
1.5 h, 90:10, 98%
20 min, 93:7, 99%
5cc
20 h, 91:9, 92%
1 h, 91;9, 97%
1.5 h, 94:6, 90%
20 min, 95:5, 99%
O
O
O
S
S
HN TIPP
S
O
S
HN TIPP
HN TIPP
N
TIPP
ꢀ40 ꢁC
F3C
Cl
F3C
rt
F3C
OMe
12cd
10cd
11cd
F3C
1.5 h, 87:13, 98%
20 min, 91:9, 99%
1.5 h, 87:13, 97%
20 min,91:9, 99%
5cd
2 h, 91:9, 98%
1 h, 91:9, 99%
O
O
S
S
HN TIPP
HN TIPP
O
S
N
TIPP
ꢀ40 ꢁC
MeO
Cl
MeO
rt
12ce
10ce
MeO
ce
20 h, >95:5, 56%
40 min,>95:5, 98%
20 h,>95:5, 87%
1 h, >95:5, 94%
aConversion is based on 1H NMR analysis and verified by the isolated yields, which closely correlate to the reported conversions.
bDiastereomeric ratio (dr) determined by 1H NMR analysis of the benzylic proton and/or secondary amine proton of the crude product. The 95:5 ratio indicates that the other
diastereomer was not detected.
cThe reaction was first conducted at ꢀ40 ꢁC for about 4e6 h and then warmed slowly to rt and stirred for 15 h.
increase in stereoselectivity while performing the reactions at am-
bient temperatures as compared to cryogenic conditions. Selected
examples include the selectivity for the reaction of phenyl Grignard
reagent 7 with p-trifluoromethylphenyl sulfinylimine 5cd in the
synthesis of 10cd increased from 74% de to 82% de and reaction of p-
methoxyphenyl Grignard reagent 8 with 5cd in the synthesis of 11cd
increased from 75% de to 82% de. More profoundly, the selectivity
improved from 70% de to >90% de in the reaction of p-chlorophenyl
magnesium bromide 9 with sulfinylimine 5ca.
The opposite diastereomers can be readily accessed with im-
proved selectivity by switching the nucleophile and electrophile
components. It was observed that in each pair of the reactions the
weaker nucleophile leads to a slightly improved stereoselectivity
when the reaction was performed at ambient temperature. For ex-
ample, the addition of phenyl magnesiumbromide 7 to 5cb provided
10cb (93:7 dr) and the synthesis of the opposite diastereomer 12ca
byaddition of p-chlorophenyl magnesiumbromide 9 to5ca gavea dr
>95:5. Similarly, addition of p-methoxylphenyl magnesium

Z. Han et al. / Tetrahedron 67 (2011) 7035e7041
7039
bromide 8 to 5cb provided 11cb (92:8 dr), and the synthesis of the
opposite diastereomer 12ce by addition of p-chlorophenyl magne-
sium bromide 9 to 5ce gave a dr >95:5.
Through the development of the chemistry with a focus on the
effects of temperature, a mild and efficient process was identified.
Higher conversions, reaction rates, and stereoselectivities were
obtained in the synthesis of diarylmethylamines by conducting the
reactions in toluene at ambient temperatures as compared to
cryogenic conditions. The chiral auxiliary TIPPSA provides im-
proved stereoselectivity as compared to t-BSA in the synthesis of
diverse diary methylamines. Additionally, calculations were per-
formed to determine the equatorial preference for the TIPP group in
a cyclohexane ring system to be 14.6 kcal/mol and this is greater
than the equatorial preference for the tert-butyl functionality. In
accordance with the DaviseEllman model for the organometallic
addition to chiral sulfinylimines, the greater equatorial preference
of the TIPP group accounts for the increased stereocontrol with this
auxiliary.
Considering the improved selectivity of triisopropylbenzene-
sulfinylimines as compared to the tert-butanesulfinyl- and p-tolue-
nesulfinylimines counterparts, a series of computations on these
substrates were performed. DaviseEllman proposes a chair-like
transition state20 (Scheme 1) to explain the origin of enantiose-
lectivity in the organometallic addition to the sulfinylimines. The
resulting stereoselectivity for the reaction will depend on the sub-
strate and reaction conditions utilized. As for Grignard reagent ad-
ditions, a six-membered ring transition statewith Mg coordinated to
the oxygen of the sulfinyl group was proposed. In this transition
state, the bulky tert-butyl group is proposed to occupy the less
hindered equatorial position thus directing the nucleophilic attack
through the corresponding ring transition state. Reduced selectivity
is observed once this six-membered ring transition state was in-
terfered by coordinating solvents, such as Et2O or THF. In conjunc-
tion with this model, in which the chiral substituent on the sulfinyl
occupies the equatorial position, we can relate the enantiofacial
control by the relative preference of each substitute to occupy the
equatorial position of a cyclohexyl-ring system. This trend appears
to hold true for the p-toluene, tert-butyl, and TIPP sulfinylimines
(Table 4). The calculated energy difference between the equatorial
and axial orientations for the p-toluene and tert-butyl (B3LYP 6-31*)
substituents are 3.5 and 5.5 kcal/mol. These values are in close
agreement with reported values of 2.9 for a phenyl substituent and
>4.5 kcal/mol for the tert-butyl, respectively.21 However for the TIPP
group, due to the appended ortho-isopropyl functionalities on the
benzene ring, the preference for equatorial orientation is greater at
14.6 kcal/mol (B3LYP 6-31*).21,22 The high equatorial presence for
the TIPP substituent can be attributed to the appended bulky ortho
iso-propyl groups, which are drawn in close proximity to the ring
system in the axial conformer. This effect is evident in the compar-
ison of the de values in Table 4, which could suggest that the ster-
eoselectivities are increased as the equatorial preference of the
substituent was augmented.23
4. Experimental
4.1. General information
1H NMR and 13C NMR spectra were recorded in deuterio-
chloroform on 400/500 MHz NMR spectrometers. Chemical shifts
were reported in parts per million (ppm) from tetramethylsilane
with the solvent resonance as the internal standard (CDCl3:
7.26 ppm for 1H NMR, 77.0 ppm for 13C NMR; CD3OD: 3.31 ppm for
1H NMR). Abbreviations for signal coupling are as follows:
s¼singlet, d¼doublet; t¼triplet, q¼quartet, dd¼doublet of dou-
blets, sep¼septet m¼multiplet. High resolution mass spectrum
(ES, positive) was determined on a Thermo LTQ FT Ultra Mass
Spectrometer. All materials were purchased from commercial
suppliers and used without further purification unless otherwise
noted.
4.2. Synthesis of sulfinylimines3
The characterization data of the following compounds 5aa,1,12
5ba,1,12 and 5ca1,12 match that have been reported.
O-
S+
O-
S+
H
4.2.1. (RS)-N-(4-Chlorobenzylidene)-2,4,6-triisopropylbenzenesulfi-
R2MgBr
R1
R2
N
R
HN
R
S
N
namide, 5cb. 1H NMR (400 MHz, CDCl3)
d
1.13 (d, J¼6.8 Hz, 6H), 1.24
R
M
R1
H
R1
R2
O
(d, J¼6.9 Hz, 6H), 1.28 (d, J¼6.8 Hz, 6H), 2.89 (sep, J¼6.9 Hz,1H), 3.82
(sep, J¼6.8 Hz, 2H), 7.08 (s, 2H), 7.42 (d, J¼8.5 Hz, 2H), 7.78 (d,
Scheme 1. DaviseEllman’s proposed model for the organometallic addition to chiral
sulfinylimines.21
J¼8.5 Hz, 2H), 8.80 (s, 1H); 13C NMR (100 MHz, CDCl3)
d 23.7, 23.7,
24.0, 24.3, 27.9, 34.4, 123.0, 129.3, 130.5, 132.8, 134.4, 138.5, 149.7,
152.9, 159.9; HRMS calculated for C22H29NOSCl (Mþ1): 390.1658;
found: 390.165 (0.357 ppm).
Table 4
Equatorial preferences (kcal/mol) of tert-butyl, p-toluene, and the TIPP groups
4.2.2. (RS)-N-(4-Fluorobenzylidene)-2,4,6-triisopropylbenzenesulfi-
namide, 5cc. 1H NMR (400 MHz, CDCl3)
d
1.14 (d, J¼6.8 Hz, 6H), 1.24
(d, J¼6.9 Hz, 6H), 1.28 (d, J¼6.8 Hz, 6H), 2.89 (sep, J¼6.9 Hz, 1H),
3.84 (sep, J¼6.8 Hz, 2H), 7.09 (s, 2H), 7.13 (t, J¼8.6 Hz, 2H), 7.86 (dd,
J¼5.5, 8.8 Hz, 2H), 8.80 (s, 1H); 19F NMR (376 MHz, CDCl3)
Substituent
B3LYP 6-31*
G (kcal/mol)
Literature
G (kcal/mol)22
deb
D
D
d
ꢀ106.05; 13C NMR (100 MHz, CDCl3)
d 23.7, 23.7, 24.0, 24.3, 27.9,
p-Toluene
tert-Butyl
TIPP
3.5
5.5
14.6
2.9a
>4.5
NA
30%
74%
86%
34.3, 116.1, 116.3, 122.9, 130.7, 130.8, 131.4, 131.5, 134.5, 149.7, 152.8,
159.8, 163.9, 166.5; HRMS calculated for C22H29NOSF (Mþ1):
374.1954; found: 374.1949 (0.183 ppm).
a
Reported for the phenyl substituent.
de of the corresponding reaction between the phenyl sulfinylimine and
b
Grignard reagent 8.23
4.2.3. (RS)-N-(4-Trifluoromethylbenzylidene)-2,4,6-triisopropylbenz-
enesulfinamide, 5cd. 1H NMR (400 MHz, CDCl3)
d
1.14 (d, J¼6.8 Hz,
3. Conclusion
6H), 1.25 (d, J¼6.8 Hz, 6H), 1.30 (d, J¼6.8 Hz, 6H), 2.90 (sep, J¼6.9 Hz,
1H), 3.83 (sep, J¼6.8 Hz, 2H), 7.10 (s, 2H), 7.71 (d, J¼8.2 Hz, 2H), 7.97
A practical asymmetric methodology was developed for the
synthesis of a variety of diarylmethanamines via the addition of
aryl Grignard reagents to N-triisopropylbenzenesulfinylimines.
(d, J¼8.1 Hz, 2H), 8.90 (s, 1H); 19F NMR (376 MHz, CDCl3)
d
ꢀ63.00;
13C NMR (100 MHz, CDCl3)
d 23.6, 23.7, 24.0, 24.3, 28.0, 34.4, 123.0,
125.9 (q), 129.5, 133.4, 133.8, 134.0, 137.1, 149.8, 153.0, 159.9; HRMS

7040
Z. Han et al. / Tetrahedron 67 (2011) 7035e7041
calculated for C23H29F3NOS (Mþ1): 424.1922; found: 424.1918
4.79 (major, d, J¼1.9 Hz, 1H), 5.72 (minor, J¼2.8 Hz, 0.12H), 5.77
(major, d, J¼1.5 Hz, 1H), 6.62 (d, J¼8.7 Hz, 2H), 7.08 (s, 2H), 7.17 (d,
(0.191 ppm).
J¼9.0 Hz, 2H), 7.58e7.62 (m, 4H); 13C NMR (400 MHz)
d 23.8, 24.2,
4.2.4. (RS)-N-(4-Methoxybenzylidene)-2,4,6-triisopropylbenzene-
24.4, 28.2, 34.4, 40.4, 61.1, 112.6, 116.7, 123.2, 125.4e125.5 (m), 128.1,
128.3, 129.1, 137.5, 145.7, 148.0, 150.3, 152.2; HRMS calculated for
C31H40F3N2OS (Mþ1): 545.2813; found: 545.2809 (0.280 ppm).
sulfinamide, 5ce. 1H NMR (400 MHz, CDCl3)
d
1.15 (d, J¼6.8 Hz, 6H),
1.24 (d, J¼6.8 Hz, 6H),1.29 (d, J¼6.8 Hz, 6H), 2.89 (sep, J¼6.9 Hz,1H),
3.85 (s, 3H), 3.87 (sep, J¼6.8 Hz, 2H), 6.94 (d, J¼8.8 Hz, 2H), 7.08 (s,
2H), 7.80 (d, J¼8.8 Hz, 2H), 8.76 (s, 1H); 13C NMR (100 MHz, CDCl3)
Compound 7ce: 1H NMR (500 MHz, CDCl3)
d
1.20 (d, J¼6.9 Hz,
6H),1.23 (d, J¼6.9 Hz, 6H),1.26 (d, J¼6.6 Hz, 6H), 2.86 (sep, J¼7.0 Hz,
1H), 2.86 (s, 6H), 3.77 (s, 3H), 3.96 (br s, 2H), 4.74 (minor, d,
J¼2.9 Hz, 0.07H), 4.76 (major, d, J¼1.8 Hz,1H), 5.65 (minor, J¼2.8 Hz,
0.07H), 5.67 (major, d, J¼1.6 Hz, 1H), 6.62 (d, J¼8.8 Hz, 2H), 6.73 (d,
J¼8.4 Hz, 2H), 6.86 (d, J¼8.6 Hz, 2H), 7.06 (s, 2H), 7.40 (d, J¼8.7, 2H);
d
23.7, 23.7, 24.0, 24.3, 27.9, 34.3, 55.4, 114.3, 122.8, 127.5, 131.2,
135.0, 149.6, 152.6, 160.3, 162.9; HRMS calculated for C23H32NO2S
(Mþ1): 385.2154; found: 386.214 (0.316 ppm).
4.3. General procedure for the Grignard addition to
13C NMR (400 MHz)
d 23.8 (2C), 24.3 (2C), 24.5 (2C), 28.1 (2C), 34.4,
sulfinylimines at ambient temperatures
40.6 (2C), 55.3, 61.1, 112.6 (2C), 113.8, 123.1 (2C), 128.0 (2C), 129.1
(2C), 129.2 (2C), 130.6, 133.3, 137.9, 148.0 (2C), 150.1, 151.8, 159.1;
HRMS calculated for C31H43N2O2S (Mþ1): 507.3045; found:
507.3041 (0.301 ppm).
To a stirred solution of sulfinylarylaldimine (2e3 mmol) in tol-
uene (1.0 M) under an argon atmosphere at rt was added the
Grignard reagent dropwise and the reaction was monitored by TLC.
When completed, the reaction was quenched with and the product
was extracted with EtOAc. The organic phase was separated and
dried over (Na2SO4), concentrated, and analyzed by 1H NMR. The
products were then isolated by flash silica chromatography.
Compound 10cb: 1H NMR (500 MHz, CDCl3)
d
1.19 (d, J¼6.8 Hz,
6H),1.24 (d, J¼6.8 Hz, 6H),1.26 (d, J¼6.5 Hz, 6H), 2.89 (sep, J¼7.0 Hz,
1H), 3.92 (br s, 2H), 4.77 (minor, d, J¼2.7 Hz), 4.80 (major, d,
J¼2.3 Hz, 1H), 5.75 (minor, d, J¼2.9 Hz), 5.77 (major, d, J¼2.3 Hz,
1H), 7.07 (s, 2H), 7.23e7.26 (m, 1H), 7.28e7.34 (m, 6H), 7.41e7.44
(m, 2H); 13C NMR (400 MHz)
d 23.7, 23.8, 24.1, 24.4, 28.2, 34.3, 61.3,
4.4. General procedure for the Grignard addition to
123.2, 127.1, 128.0, 128.7, 129.0, 129.5, 133.7, 137.4, 139.2, 142.0,
148.0, 152.2; HRMS calculated for C28H35NOSCl (Mþ1): 468.2128;
found: 468.2123 (0.223 ppm).
sulfinylimines at L40 ꢁC
To a stirred solution of sulfinylarylaldimine (2e3 mmol) in tol-
uene (1.0 M) under an argon atmosphere at ꢀ40 ꢁC (dry ice/CH3CN)
was added the Grignard reagent dropwise. The progress of the re-
actions was monitored by TLC analysis. If the reaction was not
complete within 4e6 h, the reaction was allowed to warm to rt and
stirred overnight. The reaction was then quenched with water and
the mixture was extracted with EtOAc. The organic phase was
separated, dried over Na2SO4, concentrated, and analyzed by 1H
NMR.
Compound 10cc: 1H NMR (500 MHz, CDCl3)
d
1.19 (d, J¼6.7 Hz,
6H), 1.24 (d, J¼6.8 Hz, 6H), 1.25 (d, J¼7.2 Hz, 6H), 2.88 (sep,
J¼7.1 Hz, 1H), 3.92 (br s, 2H), 4.76 (minor, d, J¼2.2 Hz), 4.82
(major, d, J¼1.8 Hz 1H), 5.76 (minor), 5.77 (major, d, J¼1.6 Hz, 1H),
7.04 (t, J¼8.5 Hz, 2H), 7.07 (s, 2H), 7.22e7.26 (m, 1H), 7.29e7.35
(m, 4H), 7.43e7.47 (m, 2H); 13C NMR (400 MHz)
d 23.7, 23.8, 24.1,
24.4, 28.2, 34.3, 61.3, 115.4, 115.6, 123.2, 127.1, 128.0, 128.9, 129.7,
129.8, 136.3, 137.4, 142.2, 148.0, 152.2, 161.2, 163.6; HRMS calcu-
lated for C28H35NOSF (Mþ1): 452.2423; found: 452.2419
(0.218 ppm).
Compound 7ca: 1H NMR (500 MHz, CDCl3)
d
1.19 (d, J¼6.9 Hz,
6H), 1.23 (d, J¼6.7 Hz, 6H), 1.26 (d, J¼6.7 Hz, 6H), 2.85 (s, 6H) 2.87
(sep, J¼7.0 Hz, 1H), 2.90 (s, 6H), 3.95 (br s, 2H), 4.78 (major, d,
J¼1.9 Hz, 1H), 4.80 (minor, d, J¼2.5 Hz, 0.10H), 5.69 (minor, 2.2 Hz,
0.10H), 5.71 (major, d, J¼1.8 Hz, 1H), 6.62 (d, J¼8.8 Hz, 2H), 7.07 (s,
2H), 7.19 (d, J¼9.0 Hz, 2H), 7.31 (t, J¼7.8 Hz, 2H), 7.46 (d, J¼7.9 Hz,
Compound 10cd: 1H NMR (500 MHz, CDCl3)
d
1.19 (d, J¼6.7 Hz,
6H),1.24 (d, J¼7.0 Hz, 6H),1.26 (d, J¼6.6 Hz, 6H), 2.88 (sep, J¼6.9 Hz,
1H), 3.92 (br s, 2H), 4.81 (minor, d, J¼3.3 Hz), 4.84 (major, d,
J¼2.4 Hz, 1H), 5.82 (minor, d, J¼3.15 Hz), 5.85 (major, d, J¼2.3 Hz,
1H), 7.08 (s, 2H), 7.24e7.27 (m, 1H), 7.29e7.35 (m, 4H), 7.62 (s, 4H);
2H); 13C NMR (400 MHz)
d
23.8, 24.3, 24.5, 28.2, 34.4, 40.5, 61.7,
13C NMR (400 MHz)
d 23.7, 23.8, 24.1, 24.4, 28.2, 34.3, 61.5, 123.2,
112.7, 123.1, 128.1, 128.2, 128.3, 128.5, 129.1, 130.3, 137.9, 141.3, 148.0,
150.1, 152.0; HRMS calculated for C30H41N2O2S (Mþ1): 477.2940;
found: 477.2936 (0.288 ppm).
125.5, 125.6, 125.9, 126.9, 127.2, 128.1, 128.2, 128.4, 129.1, 137.2,
141.6, 144.8, 148.0, 152.3; HRMS calculated for C29H35NOF3S (Mþ1):
502.2391; found: 502.2388 (0.382 ppm).
Compound 7cb: 1H NMR (500 MHz, CDCl3)
d
1.19 (d, J¼6.9 Hz,
Compound 10ce: 1H NMR (500 MHz, CDCl3)
d
1.19 (d, J¼6.8 Hz,
6H),1.24 (d, J¼6.7 Hz, 6H), 1.26 (d, J¼6.7 Hz, 6H), 2.87 (sep, J¼7.0 Hz,
1H), 2.90 (s, 6H), 3.92 (br s, 2H), 4.72 (minor, d, J¼2.9 Hz, 0.11H),
4.76 (major, d, J¼1.8 Hz, 1H), 5.65 (minor, J¼2.8 Hz, 0.09H), 5.69
(major, d, J¼1.4 Hz, 1H), 6.62 (d, J¼8.6 Hz, 2H), 7.07 (s, 2H), 7.16 (d,
J¼8.7 Hz, 2H), 7.30 (d, J¼8.5 Hz, 2H), 7.42 (d, J¼8.5 Hz, 2H); 13C NMR
6H),1.24 (d, J¼6.9 Hz, 6H),1.26 (d, J¼6.5 Hz, 6H), 2.87 (sep, J¼6.8 Hz,
1H), 3.70 (s, 3H), 3.92 (br s, 2H), 4.77 (minor, d, J¼2.50 Hz, 0.04H),
4.81 (major, d, J¼2.53 Hz, 1H), 5.74 (d, J¼2.35 Hz, 1H), 6.88 (d,
J¼8.3 Hz, 2H), 7.07 (s, 2H), 7.20e7.24 (m, 1H), 7.29 (t, J¼7.8 Hz, 2H),
7.35e7.4 (m, 4H); 13C NMR (400 MHz)
d 23.7, 23.8, 24.1, 24.5, 28.1,
(400 MHz)
d
23.8, 24.2, 24.5, 28.1, 34.3, 40.5, 60.8, 112.6, 123.2,
34.3, 55.3, 61.6, 114.0, 123.1, 127.1, 127.7, 128.8, 129.3, 132.5, 137.7,
142.7, 148.0, 152.0, 159.3; HRMS calculated for C29H38NO2S (Mþ1):
464.2623; found: 464.2619 (0.176 ppm).
128.0, 128.6, 129.4, 129.6, 133.3, 137.6, 139.9, 148.0, 150.2, 152.2;
HRMS calculated for C30H40N2OClS (Mþ1): 512.2550; found:
511.2546 (0.391 ppm).
Compound 11ca: 1H NMR (500 MHz, CDCl3)
d
1.19 (d, J¼6.8 Hz,
Compound 7cc: 1H NMR (500 MHz, CDCl3)
d
1.19 (d, J¼6.7 Hz,
6H),1.24 (d, J¼6.9 Hz, 6H),1.26 (d, J¼6.5 Hz, 6H), 2.87 (sep, J¼6.8 Hz,
1H), 3.70 (s, 3H), 3.92 (br s, 2H), 4.77 (major, d, J¼2.50 Hz 1H), 4.81
(minor, d, J¼2.53 Hz), 5.74 (d, J¼2.35 Hz, 1H), 6.82 (d, J¼8.3 Hz, 2H),
7.07 (s, 2H), 7.25e7.30 (m, 3H), 7.34 (t, J¼7.8 Hz, 2H), 7.46 (m, 2H);
6H), 1.23 (d, J¼6.7 Hz, 6H), 1.26 (d, J¼6.3 Hz, 6H), 2.87 (m, 1H), 2.89
(s, 6H), 3.92 (br s, 2H), 4.72 (minor, s, 0.09H), 4.76 (major, s, 1H),
5.66 (minor, s, 0.09H), 5.69 (major, s,1H), 6.63 (d, J¼8.6 Hz, 2H), 7.06
(s, 2H), 7.17 (d, J¼8.4 Hz, 2H), 7.24 (m, 2H), 7.45 (m, 2H); 13C NMR
13C NMR (400 MHz)
d 23.7, 23.8, 24.1, 24.5, 28.1, 34.3, 55.3, 61.6,
(400 MHz)
d
23.8, 24.2, 24.5, 28.1, 34.3, 40.4, 40.6, 60.9, 112.6, 112.7,
113.9, 114.2, 123.1, 127.7, 128.0, 128.4, 128.5, 129.5, 134.7, 137.8, 141.0,
148.0 (2C), 152.0, 159.1; HRMS calculated for C29H38NO2S (Mþ1):
464.2623; found: 464.2619 (0.306 ppm).
123.1,128.0,129.1,129.6,129.7,129.9,137.0,137.6,148.0,150.1,152.0;
HRMS calculated for C30H39FN2OS: 494.2467.
Compound 7cd: 1H NMR (500 MHz, CDCl3)
6H), 1.24 (d, J¼6.8 Hz, 6H), 1.27 (d, J¼6.5 Hz, 6H), 2.88 (sep, J¼7.0 Hz,
1H), 2.88 (s, 6H), 3.92 (br s, 2H), 4.78 (minor, d, J¼3.0 Hz, 0.12H),
d
1.20 (d, J¼6.8 Hz,
Compound 11cb: 1H NMR (500 MHz, CDCl3)
6H), 1.24 (d, J¼7.0 Hz, 6H), 1.26 (d, J¼6.9 Hz, 6H), 2.88 (sep, J¼7.0 Hz,
1H), 3.75 (s, 3H), 3.92 (br s, 2H), 4.76 (d, J¼2.2 Hz, 1H), 5.70 (minor,
d
1.19 (d, J¼6.8 Hz,

Z. Han et al. / Tetrahedron 67 (2011) 7035e7041
7041
d, J¼2.7 Hz), 5.72 (major, J¼2.0 Hz, 1H), 6.83 (d, J¼8.7 Hz, 2H), 7.07
(s, 2H), 7.24 (d, J¼8.7 Hz, 2H), 7.32 (d, J¼8.1 Hz, 2H), 7.41 (d,
(2C), 129.0 (2C), 129.2 (2C), 132.2, 133.5, 137.5, 141.2, 148.0 (2C),
152.1, 159.4; HRMS calculated for C29H37ClNO2S (Mþ1): 498.2234;
found: 498.2230 (0.310 ppm).
J¼8.43 Hz, 2H); 13C NMR (400 MHz)
d 23.7, 23.8, 24.2, 24.4, 28.1,
34.3, 55.3, 60.8, 114.3, 123.2, 128.4, 128.7, 129.3, 129.4, 133.5, 134.2,
137.5, 139.5, 148.0, 152.2, 159.3; HRMS calculated for C29H37NO2SCl
(Mþ1): 498.2324; found: 498.2229 (0.109 ppm).
Acknowledgements
Compound 11cc: 1H NMR (500 MHz, CDCl3)
d
1.20 (d, J¼6.9 Hz,
We thank Dr. Fenghe Qiu and Scott for HRMS analysis.
6H), 1.24 (d, J¼7.0 Hz, 6H), 1.26 (d, J¼6.9 Hz, 6H), 2.88 (sep, J¼6.9 Hz,
1H), 3.75 (s, 3H), 3.92 (br s, 2H), 4.75 (minor, d, J¼2.6 Hz, 0.08H),
4.77 (major, d, J¼2.1 Hz, 1H), 5.72 (minor, d, J¼2.7 Hz, 0.08H), 5.73
(major, 2.1 Hz, 1H), 6.83 (d, J¼8.8 Hz, 2H), 7.03 (t, J¼8.7 Hz, 2H), 7.07
(s, 2H), 7.26 (d, J¼8.7 Hz, 2H), 7.42e7.47 (m, 2H); 13C NMR
Supplementary data
Additional procedures, spectral data and characterizations (1H
and 13C NMR), and HRMS of all new products. Supplementary data
associated with this article can be found in online version at
doi:10.1016/j.tet.2011.07.019.
(400 MHz) d 23.8, 24.2, 24.4, 28.1, 34.3, 55.3, 60.8, 114.3, 115.3,155.5,
123.2, 128.3, 129.6, 129.7, 134.4, 136.6 (d, J¼3.2 Hz, 1C), 137.5, 148.0,
152.1, 159.2, 163.6; HRMS calculated for C29H37NO2SF (Mþ1):
482.2529; found: 482.2524 (0.091 ppm).
References and notes
Compound 11cd: 1H NMR (500 MHz, CDCl3)
d
1.20 (d, J¼7.0 Hz,
6H),1.24 (d, J¼6.9 Hz, 6H),1.26 (d, J¼6.6 Hz, 6H), 2.88 (sep, J¼6.8 Hz,
1H), 3.75 (s, 3H), 3.92 (br s, 2H), 4.80 (d, J¼2.2 Hz, 1H) 5.77 (minor,
d, J¼2.7 Hz, 0.11H), 5.81 (major, d, J¼2.0 Hz, 1H), 6.84 (d, J¼8.7 Hz,
2H), 7.08 (s, 2H), 7.25 (d, J¼8.6 Hz, 2H), 7.61 (s, 4H); 13C NMR
1. (a) Mukade, T.; Dragoli, D. R.; Ellman, J. A. J. Comb. Chem. 2003, 5, 590 and the
references cited herein; (b) Bloch, R. Chem. Rev. 1998, 98, 1407; Bobayashi, S.;
Ishitani, H. Chem. Rev. 1999, 99, 1069; (c) Li, S.-W.; Batey, R. Chem. Commun.
2004, 1382; (d) Nagasawa, M.; Kawase, N.; Tanaka, N.; Nakamura, H.; Tsuzuike,
N.; Murata, M. PCT Int. Appl. 2005, 248pp; (e) Moritani, Y.; Kokubo, S.; Tsuboi,
Y.; Okagaki, C.; Oku, A.; Hirano, N. Jpn. Kokai Tokkyo Koho, 2007, 222pp; (f)
Jaquith, J. PCT Int. Appl. 2010, 103pp.
2. (a) Senanayake, C. H.; Krishnamurthy, D.; Lu, Z.-H.; Han, Z.; Gallou, I. Aldrichi-
mica Acta 2005, 38, 93 and the references cited herein; (b) Senanayake, C. H.;
Han, Z.; Krishnamurthy, D. In Organicsulfur Chemistry in Asymmetruc Synthesis;
Toru, T., Bolm, C., Eds.; Wiley-VCH GmbH & KGaA: 2008; p 233.
3. (a) Han, Z.; Krishnamurthy, D.; Grover, P.; Fang, Q. K.; Pflum, D. A.; Senanayake,
C. H. Tetrahedron Lett. 2003, 44, 4195; (b) It was observed in the Ref. 3a that
toluene gave better selectivity as compared to other solvents.
4. (a) Plobeck, N.; Powell, D. Tetrahedron: Asymmetry 2002, 12, 303; (b) Chan, W.-
H.; Lee, A. W. M.; Xia, P. F.; Wong, W. Y. Tetrahedron Lett. 2000, 41, 5725; (c)
Baker, R. K.; Hale, J. J.; Miao, S.; Rupprecht, K. M. U.S. Patent Appl. 2007123505.
5. Batey, R. A.; Bolshan, Y. Org. Lett. 2005, 7, 1481.
6. Weix, D. J.; Shi, Y.; Ellman, J. A. J. Am. Chem. Soc. 2005, 127, 1092.
7. Boebel, T.; Hartwig, J. F. Tetrahedron 2008, 64, 6824.
8. Nakagawa, H.; Rech, J. C.; Sindelar, R. W.; Ellman, J. A. Org. Lett. 2007, 9, 5155.
9. Hayashi, T.; Kawai, M.; Tokunaga, N. Angew. Chem., Int. Ed. 2004, 43, 6125.
10. Ma, G.-N.; Zhang, T.; Shi, M. Org. Lett. 2009, 11, 875.
11. (a) Kuriyama, M.; Soeta, T.; Hao, X.; Chen, Q.; Tomioka, K. J. Am. Chem. Soc. 2004,
126, 8128; (b) Tokunaga, N.; Otomaru, Y.; Okamoto, K.; Ueyama, K.; Shintani, R.;
Hayashi, T. J. Am. Chem. Soc. 2004, 126, 13585.
12. Hermanns, N.; Dahman, S.; Bolm, C.; Braese, S. Angew. Chem., Int. Ed. 2002, 41,
3692.
13. Maji, M. S.; Frohlich, R.; Studer, A. Org. Lett. 2008, 10, 1847.
14. Pflum, D. A.; Krishnamurthy, D.; Han, Z.; Wald, S. A.; Senanayake, C. H. Tetra-
hedron Lett. 2002, 43, 923.
15. (a) Han, Z.; Krishnamurthy, D.; Grover, P.; Fang, Q. K.; Senanayake, C. H. J. Am.
Chem. Soc. 2002, 124, 7880; (b) Han, Z.; Krishnamurthy, D.; Grover, P.; Fang, Q.
K.; Su, X.; Wilkinson, H. S.; Lu, Z.-H.; Magiera, D.; Senanayake, C. H. Tetrahedron
2005, 61, 6386; (c) Use of toluene as solvent would provide better selectivity as
reported in Ref. (a).
16. (a) Zhou, P.; Chen, B.-C.; Davis, F. A. Tetrahedron 2004, 60, 8003; (b) Ellman, J. A.
Pure Appl. Chem. 2003, 75, 39; (c) Davis, F. A. J. Org. Chem. 2006, 71, 8993.
17. Kong, J.-R.; Cho, C.-W.; Krische, M. J. J. Am. Chem. Soc. 2005, 127, 11269.
18. David, F. A.; Chai, J. ARKIVOC 2008, 190.
(400 MHz) d 23.7, 23.8, 24.1, 24.4, 28.2, 34.3, 55.3, 61.0, 114.4, 123.2,
125.5 (q, J¼3.75 Hz), 127.1, 128.2, 128.9, 133.8, 137.4, 145.2, 148.0,
152.3, 159.4; HRMS calculated for C30H37NO2F3S (Mþ1): 532.2497;
found: 532.2493 (0.314 ppm).
Compound 12ca: 1H NMR (500 MHz, CDCl3)
d
1.19 (d, J¼6.9 Hz,
6H),1.24 (d, J¼6.8 Hz, 6H),1.26 (d, J¼6.5 Hz, 6H), 2.87 (sep, J¼6.8 Hz,
1H), 3.92 (br s, 2H), 4.78 (major, d, J¼2.7 Hz, 1H), 4.81 (minor, d,
J¼2.3 Hz, 0.07H), 5.74 (major, d, J¼2.7 Hz 1H), 5.77 (minor, d,
J¼2.3 Hz, 0.07H), 7.08 (s, 2H), 7.23e7.26 (m, 1H), 7.28e7.34 (m, 6H),
7.41e7.44 (m, 2H); 13C NMR (400 MHz)
d 23.7, 23.8, 24.2, 24.4, 28.2,
34.3, 61.7, 123.2, 127.9, 128.1, 128.6, 128.7, 129.0, 133.6, 137.5, 140.3,
141.0, 148.0, 152.2; HRMS calculated for C28H35ClNOS (Mþ1):
468.21218; found: 468.2124 (0.297 ppm).
Compound 12cc: 1H NMR (500 MHz, CDCl3)
d
1.20 (d, J¼6.6 Hz,
6H),1.24 (d, J¼6.5 Hz, 6H),1.25 (d, J¼5.9 Hz, 6H), 2.88 (sep, J¼6.9 Hz,
1H), 3.92 (br s, 2H), 4.75 (minor, d, J¼2.2 Hz, 0.09H), 4.77 (major, d,
J¼1.9 Hz 1H), 5.74 (d, J¼2.5 Hz, 1H), 7.04 (t, J¼8.7 Hz, 2H), 7.08 (s,
2H), 7.28 (2, 4H), 7.38e7.43 (m, 2H); 13C NMR (400 MHz)
d 23.7,
23.8, 24.1, 24.4, 28.1, 34.3, 60.9,115.5,115.7,123.2, 128.5, 129.1,129.6,
129.7, 133.8, 135.9, 136.0, 137.2, 140.7, 148.0, 152.3; HRMS calculated
for C28H34ClFNOS (Mþ1): 468.2034; found: 468.2030 (0.351 ppm).
Compound 12cd: 1H NMR (500 MHz, CDCl3)
d
1.20 (d, J¼7.0 Hz,
6H),1.24 (d, J¼6.7 Hz, 6H),1.26 (d, J¼6.2 Hz, 6H), 2.89 (sep, J¼6.8 Hz,
1H), 3.92 (br s, 2H), 4.80 (d, J¼2.6 Hz, 1H), 5.81 (minor, d, J¼2.8 Hz,
INCON), 5.82 (major, d, J¼2.7 Hz, 1H) 7.09 (s, 2H), 7.29 (s, 4H),
7.56e7.64 (m, 4H); 13C NMR (400 MHz)
d 23.8 (2C), 24.1 (2C), 24.4
(2C), 28.1 (2C), 34.3, 54.6, 123.0 (4C), 127.1 (2C), 127.1, 128.5 (2C),
128.6, 128.7, 129.4, 131.1, 132.4, 138.0, 142.8, 147.7 (2C), 151.8; HRMS
calculated for C29H34F3ClNOS (Mþ1): 536.2002; found: 536.1998
(0.325 ppm).
19. Davis, F. A.; Song, M. Org. Lett. 2007, 9, 2413.
20. Cogan, D. A.; Liu, G.; Ellman, J. Tetrahedron 1999, 55.
21. Calculations performed with the Spartan ’08 program on a Windows XP PC
employing the B3LYP 6-31* level of theory.
Compound 12ce: 1H NMR (500 MHz, CDCl3)
d
1.20 (d, J¼6.9 Hz,
22. Several twist boat conformers were found at 7.5 kcal/mol higher than the
equatorial conformation. In order to obtain a more direct comparison between
the tert-butyl and TIPP substituents, the conformation of the cyclohexane ring
was constrained to match the axial tert-butyl cyclohexane system before the
conformation search.
23. The stereoselectivities for the addition of 4-methyoxyphenyl magnesium bro-
mide 8 to 5aa, 5ba, and 5ca are 84:16 dr, 62:28 dr, and 93:7 dr at ꢀ40 ꢁC and
85:15 dr, 64:36 dr, and 94:6 dr at ambient temperature, respectively.
6H), 1.24 (d, J¼6.6 Hz, 6H), 1.25 (d, J¼5.4 Hz, 6H), 2.88 (sep, J¼7.0 Hz,
1H), 3.80 (s, 3H), 3.92 (br s, 2H), 4.75 (d, J¼1.9 Hz, 1H), 5.69 (major,
d, J¼2.4 Hz, 1H), 5.73 (minor, J¼2.0 Hz), 6.88 (d, J¼8.6 Hz, 2H), 7.07
(s, 2H), 7.25e7.35 (m, 6H); 13C NMR (400 MHz)
d 23.7, 23.8, 24.2
(2C), 24.4 (2C), 28.1 (2C), 34.3, 55.3, 61.2, 114.1 (2C),123.1 (2C),128.5