Highly enantioselective (-)-sparteine-mediated lateral metalation-functionalization of remote silyl protected ortho -ethyl N, N -dialkyl aryl O -carbamates

Article abstract of DOI:10.1021/jo502561m

We report the enantioselective, lateral deprotonation of ortho-protected or functionalized tertiary N,N-dialkyl aryl O-carbamates 5-7 (Scheme 2) and meta-protected carbamates 14, 15, and 20 (Schemes 5 and 7) by s-BuLi/(-)-sparteine and subsequent quench w

Full text of DOI:10.1021/jo502561m

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Article
Highly Enantioselective (–)-Sparteine-Mediated
Lateral Metalation-Functionalization of Remote Silyl
Protected ortho-Ethyl N,N-Dialkyl Aryl O-Carbamates
Jurg Fassler, J. Adam McCubbin, Anna Roglans, Tetsutaro Kimachi, Joshua W. Hollett, Roland
W. Kunz, Michael Tinkl, Yousheng Zhang, Ruiyao Wang, Michael Campbell, and Victor Snieckus
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo502561m • Publication Date (Web): 18 Dec 2014
Downloaded from http://pubs.acs.org on February 18, 2015
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1
Highly Enantioselective (–)-Sparteine-Mediated Lateral Metalation-Functionalization of
Remote Silyl Protected ortho-Ethyl N,N-Dialkyl Aryl O-Carbamates
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†
Jürg Fässler, J. Adam McCubbin, Anna Roglans, Tetsutaro Kimachi, Joshua W. Hollett , Roland
‡
W. Kunz , Michael Tinkl, Yousheng Zhang, Ruiyao Wang, Michael Campbell and Victor
Snieckus*
Department of Chemistry, University of Waterloo, Waterloo, Ontario, N2L 3G1Canada
*
Department of Chemistry, Queen’s University, Kingston, Ontario, K7L 3N6 Canada
†
Department of Chemistry, University of Winnipeg, Winnipeg, Manitoba, R3B 2E9 Canada
‡
Institute of Organic Chemistry, University of Zurich, Winterthurerstr. 190, CH-8057 Zurich,
Switzerland
*victor.snieckus@chem.queensu.ca
Dedicated to Professor Bob Gawley: in Memoriam
Table of Contents Graphic:
remote
PG
Li
O
E
O
R Si
3
O
NR2
R Si
3
O
NR2
all retentive
(S)
Hpro(S)
up to:
96% yield
99:1 er
Me
Me
via:
s-BuLi
(-)-sparteine
N
N
o
Bu
H
O (Z)
E
-
78 C
rate &
enantio-
determining
Li
Si
NR2
O
Me
config. stable
H
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Abstract: We report on the enantioselective, lateral deprotonation of ortho-protected or
functionalized tertiary N,N-dialkyl aryl O-carbamates 5-7 (Scheme 2) and meta-protected
carbamates 14, 15, 20 (Schemes 5 and 7) by s-BuLi/(–)-sparteine and subsequent quench with a
variety of electrophiles to give products 11, 12, and 13 and 16, 17 and 21 in yields up to 96% and
enantiomeric ratios up to 99:1. The influences of organolithium reagents, ratio of
organolithium/(–)-sparteine pair versus N,N-dialkyl aryl O-carbamate starting materials,
temperature, solvents, electrophiles, substituents located ortho or meta to the O-carbamate moiety
and O-carbamate N-substituents were investigated. The identical absolute configuration of the
stereogenic center of the major enantiomers of the products, as established by single crystal X-ray
analysis for substrates (S)-19, (S)-21a and (S)-11c, provides evidence for a consistent
stereochemical course in the enantioselective deprotonation. Mechanistic investigations,
including an estimate of the configurational stability of the benzyllithium species 9 (starting from
0
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2e, Scheme 8) and 23 (starting from 17e, Scheme 9), both derived by tin-lithium exchange, and
26 (starting from 20, Scheme 10), are reported. The experimental results, together with
semiempirical molecular orbital calculations (PM3/SMD), are consistent with a process in which
enantioinduction occurs in the deprotonation step (Scheme 11).
Introduction
1
2
Since the original work of Nozaki and Guetté four decades ago and the pioneering contributions
3
4
of the groups of Hoppe and, subsequently, Beak, the application of the enantiopure lupine
5
alkaloid (–)-sparteine as an additive in “carbanionic” enantioselective synthesis has gained
considerable prominence. Thus, the broad scope of (–)-sparteine-mediated carbanionic
3
,4,6
transformations
has been demonstrated, inter alia, in the preparation of enantioenriched
7
8
9
natural and unnatural amino acids, asymmetric inter- and intra-molecular carbolithiations, an
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enantioselective Li-ene-reaction, the enantioselective preparation of functionalized 1,5-
1
1
12
13
cyclononadienes and anti homoaldol products, enantioselective functionalization of small
1
4
15
and medium-sized rings, the generation of P-stereogenic centres, and the enantioselective
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lithiation of unsaturated carbamates.
1
3
Subsequent to the initial observations of Nozaki and the seminal studies of Hoppe and
4
Beak, (–)-sparteine-mediated benzylic metalation has been investigated on several types of
17
derivatives 1-4 (Scheme 1), which take advantage of an α-heteroatom 1a-f, an ortho-
1
8
19
20
21
heteroatom 2, a styryl α-amino moiety 3, a β-heteroatom 4 and their coordination effects.
Scheme 1. Previous Work on Enantioselective Benzylic Metalation. 2e: this work
Li•(–)-sparteine
Z
Z
Li•(–)-sparteine
1
2
9
e
4a
2a: Z = CONR (Beak)
2
2b: Z = CONR [Cr(CO) ] (Uemura)
1
a: Z = OCONR (Hoppe)
2
b: Z = N(Me)Boc (Schlosser)
1
7b
18c
1
1c: Z = N(Ar)Boc (Beak)
1d: Z = N(Me)CONMe (no sparteine, Beak)
2
2c: Z = NPiv (Park)
3
1
7g
18d
1
7n
18b
2
1e: Z = P(O)(OMe) (no sparteine, Wiemer)
2d: Z = S*(O)Tol (no sparteine, Ruano)
2e: Z = OCONR (Snieckus) this work
1
7i
2
2
O
1
7h
(
no sparteine, Hoppe)
1f: Z =
S
N
Ar
O
(–)-sparteine•
Li
O
(
–)-sparteine•
Li
NBoc
Li
NR
3
(Beak)
4
(Beak)
1
9
20
Stimulated by these findings, we had previously investigated the (–)-sparteine-induced, highly
enantioselective preparation of planar chiral ferrocenes and their application in an asymmetric
22
23
alkylation and Pd(0)-catalyzed allylic substitution. The original studies of Clark and the
4
b
results of Beak especially motivated our work in establishing a (–)-sparteine-mediated
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enantioselective synthesis of tetrahydroisoquinolin-1-ones. Involvement in studies of the O-
2
5
carbamate as the most powerful directed metalation group (DMG) provided the impetus to
undertake the investigation of the (–)-sparteine-mediated lateral metalation of tertiary ortho-ethyl
N,N-dialkyl aryl O-carbamates. We now detail results on studies concerning O-carbamates 5-7
(Scheme 2), 14, 15, (Scheme 5), and 20 (Scheme 7) with respect to variation of conditions,
electrophiles, and ratio of organolithium/(–)-sparteine complex to starting N,N-dialkyl aryl O-
carbamate and, perhaps of particular interest, the effect of ortho and meta-substitution on the
enantioselectivity of the reaction. We thereby offer a contribution which may serve in the further
rational improvement of new methodology for asymmetric synthesis.
0
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9
0
Scheme 2. Lateral Metalation of 2-Ethyl Aryl O-Carbamates. Evading the anionic ortho Fries
Rearrangement.
R
R
O
NR'2
OCONR'2
E+
s-BuLi, –78°C
O
N
H
Li
N
N
N
H
–)-sparteine
(
5
6
7
R = MeO, R' = Et
R = TMS, R' = Et
R = TMS, R' = i-Pr
8
9
R = MeO, R' = Et
R = TMS, R' = Et
10 R = TMS, R' = i-Pr
E
R
11a TMS
1
1
1b MeS
OCONR'2
m-CPBA
1c MeSO
2
E
12a TMS
1
1
1
1
1
1
1
2b Me(CH
)
2 9
2c CH =CHCH
2
2
2d MeOCH
2
11 R = MeO, R' = Et
2e n-Bu Sn
3
12 R = TMS, R' = Et
13 R = TMS, R' = i-Pr
2f PhS
2g PhSe
2h Cl
absolute configuration determined
for compound 11c.
13a MeS
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Results and Discussion
Effect of Base and Solvent on the (–)-Sparteine-Mediated Lateral Metalation of N,N-dialkyl
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11
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2
6
aryl O-carbamates. 6-MeO- and 6-TMS- 2-ethyl phenyl diethyl O-carbamates 5 and 6 were
chosen for the initial studies in order to preclude competitive anionic ortho-Fries
25a
27
28
rearrangement and with considerations of synthetic potential in desilylation, hydrolysis, and
2
9
cross coupling reactions. (–)-Sparteine-mediated lateral metalation conditions were tested on
carbamate 6 using alkyllithiums and LDA and TMSCl as the electrophile quench (Scheme 3). A
temperature effect was noted with the n-BuLi/(–)-sparteine combination. Thus, from the reaction
at –78°C, in addition to recovery of unreacted 6, compound 12a was obtained in 16% yield and
9
2:8 er, while at –40°C, 12a was isolated in 64% yield and 82:18 er. Application of t-BuLi/(–
)
-sparteine at –78°C afforded 12a in high yield (84%) but as a racemic mixture, a result consistent
with the observation by Beak in using this base/(–)-sparteine conditions for the metalation of N-
30
Boc-pyrrolidine. While use of LDA/(–)-sparteine at –78°C gave no product, at –30°C, 12a was
obtained in 82% yield but as a racemate. Metalation using s-BuLi/(–)-sparteine (2.2 equiv/2-3 h
optimum conditions) at –78°C furnished 12a in 60% yield and 83:17 er. These conditions were
adopted in all subsequent studies as a reasonable compromise in terms of yield and
enantioselectivity at the lower temperature.
Scheme 3. (–)-Sparteine-Mediated Lateral Metalation of Compound 6. Optimization of
Enantioinduction as a Function of the Base
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6
SiMe3
SiMe3
1) R-Li/(–)-sparteine
OCONEt2
OCONEt2
temp., Et O
2
SiMe3
2
) TMSCl
6
R-Li
temp.
yield
er
12a
0
1
2
3
4
5
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9
0
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9
0
n-BuLi
n-BuLi
s-BuLi
–78°C
–40°C
–78°C
16%
64%
60%
92:8
82:18
83:17
racemic
–
absolute configuration
assigned by analogy
with compound 11c
t-BuLi
LDA
–78°C
84%
–78°C no reaction
–30°C
82%
LDA
racemic
To determine the influence of solvent, the N,N-dialkyl aryl O-carbamates 5 and 6 were metalated
under the optimized conditions in single and mixed solvent systems and the resulting
benzyllithium species were quenched with TMSCl or dimethyl disulfide (MeSSMe) to afford
compounds 11a and 12b and 11b and 13a respectively(Table 1).
Table 1. Effect of Solvent on the (–)-Sparteine-Mediated Lateral Metalation of N,N-dialkyl aryl
O-carbamates 5-7.
a
b
Entry
Starting Material
Solvent
THF
Product
11a
11a
11b
11a
11a
11a
12a
12a
12a
12a
12a
Yield, %
93
er
1
2
5
5
5
5
5
5
6
6
6
6
6
50:50
96:4
Et O
34
2
c
3
Et O
46
94:6
2
4
5
t-BuOMe
48
89:11
96:4
(i-Pr) O
50
2
6
hexanes
< 5
60
> 99:1
83:17
76:24
85:15
88:12
88:12
7
Et O
2
8
t-BuOMe
75
9
(i-Pr) O
58
2
10
hexanes
toluene
46
1
1
9
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t-BuOMe:toluene
12
6
7
12a
78
84
86:14
69:31
1
:3
c
1
3
Et O
13a
2
a
b
c
Yields of isolated products; Determined by CSP-HPLC (see Experimental Section). MeSSMe
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11
12
13
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used as electrophile.
As gleaned from Table 1, no enantioenrichment was observed when the metalation of 6-MeO-
substituted N,N-dialkyl aryl O-carbamate 5 was carried out in THF (entry 1). The absence of
enantioinduction suggests that the coordination effect of THF is competitively stronger than that
of (–)-sparteine. Unlike Et O, THF saturates the coordination sphere of the lithium cation and
2
3
1
thereby excludes complexation with a bidentate ligand such as (–)-sparteine. Although
numerous low and absent enantioinductions in (–)-sparteine-mediated transformations of
3
2
organolithium reagents in THF have been reported, several instances of moderate to high
3
3
enantioselectivities in reactions in this solvent should be noted.
In the case of acyclic ethereal solvents, moderate to high enantiomeric ratios but only moderate
yields of 11a and 11b (34-50%) were observed (entries 2-5). Attempted optimization by
3
4
increasing the reaction time resulted in side reactions. Although high er’s were observed in
hexanes (entry 6), limited solubility of 5 precluded attainment of acceptable yields. In
comparison, the more soluble 6-TMS carbamate 7 showed reasonable enantioinduction and yields
in ethereal (entries 7-9) as well as hydrocarbon (entry 10) and aromatic (entry 11) solvents. The
best result was obtained when the optimal solvents regarding yield (entry 8) and enantioinduction
(entry 11) were combined (entry 12). The results depicted in Table 2 show consistent
enantioenrichments for a variety of products resulting from carbon (12b-d) and heteroatom (12e-
h) electrophile introduction under these conditions.
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1
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2
2
2
2
2
2
2
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5
5
6
8
Table 2. Lateral Metalation-Electrophile-quench Reactions of 6 using s-BuLi/(–)-Sparteine.
+
a
E
E
Product
Yield, %
54
er
Me(CH ) Br
Me(CH2)9
12b
83:17
2
9
0
1
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0
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9
0
H C=CHCH Br
H C=CHCH
12c
12d
12e
12f
75
39
63
71
69
64
87:13
84:16
86:14
85:15
84:16
90:10
2
2
2
2
MeOCH Cl
MeOCH2
2
n-Bu SnCl
n-Bu Sn
3
3
PhSSPh
PhSeSePh
Cl CCCl
PhS
PhSe
Cl
12g
12h
3
3
a
Yields of isolated products.
The absolute configuration of the major enantiomer of 11b was established by single-crystal X-
ray crystallographic analysis of the corresponding sulfone 11c obtained by oxidation using
m-CPBA (Scheme 4, see Experimental Section).
Scheme 4. Synthesis and ORTEP plot of 11c. C-atoms not labeled, H-atoms omitted for clarity.
N
O
MeS H
OCONEt2
OMe
H
O
(
S)
m-CPBA
CH Cl
O
S
2
2
O
O
9
2%
1
1b
1
1c
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Comparative Study of Diethyl- vs Diisopropyl aryl O-Carbamates and ortho-Methoxy vs
ortho-Trimethylsilyl Substituents. A comparison of the effect of two substituents with different
electronic and steric properties (6-MeO vs 6-TMS) and the steric influence of N-substituents
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(
diethyl vs diisopropyl) is demonstrated by the results shown in Table 1. Thus, 6-MeO N,N-
diethyl O-carbamate 5 afforded 11a (entry 2) in 34% yield and 96:4 er and 11b (entry 3) in 46%
yield and 94:6 er. Under identical conditions (2.2 equiv s-BuLi/(–)-sparteine/Et O/–78°C/2 h), the
2
6
-TMS-substituted diethyl O-carbamate 6 gave 12a (entry 7, Table 1) in 60% yield and 83:17 er.
When ortho-TMS-substituted N,N-diisopropyl aryl O-carbamate 7 was subjected to the
conditions used for N,N-diethyl aryl O-carbamates 5 and 6, product 13a was isolated in 84% yield
(entry 13, Table 1), which is comparable to the yields obtained for 12a-h (Tables 1 and 2) but
with a substantially decreased er (69:31). These findings suggest that bulky substituents located
ortho to the O-carbamate moiety together with sterically demanding N-carbamate substituent lead
3
5
to a considerable loss of enantioselectivity.
Introduction of Remote Protection: The TBS-Group. Guided by these results and based on the
assumption that a bulky silyl substituent located meta to the carbamate would prevent the onset of
2
5a
the well known ortho-deprotonation and anionic Fries rearrangement, the lateral metalation of
3
6
the 5-TBS derivatives 14 and 15 was investigated (Scheme 5).
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1
1
1
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2
2
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2
2
2
2
2
2
3
3
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3
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3
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4
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4
4
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5
5
5
5
5
5
6
1
0
Scheme 5. Lateral Metalation of 2-Ethyl Aryl O-Carbamates. The Effect of Remote Protection.
for R' = Et, E+ = TMSCl:
for R' = i-Pr:
TBS
OCONR'2
TBS
OCONEt
TMS
2
TBS
OCON(i-Pr)
2
1
2
) s-BuLi/(–)-sparteine
–
78°C, 2 h
E
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
) E
14 R' = Et
R' = i-Pr
16a
17
1
5
36% yield
9
2:8 er
E
R' = i-Pr
sequential lateral metalation (i)
17a TMS
17b CH =CHCH
2
2
17c MeOCH
17d n-Bu Sn
2
TBS
OCON(i-Pr)2
3
1
1
1
1
1
7e Me Sn
3
SMe
7f PhS
7g MeS
7h PhSe
7i OH
1
7g
1
8
6% yield
6:14 er
i: 1.05 equiv s-BuLi/(–)-sparteine, Et O, –78°C, 2 h, then 1.05 equiv MeSSMe, –78°C, 1 h,
2
then 1 equiv s-BuLi/(–)-sparteine, –78°C, 1 h.
3
7
Gratifyingly, when compound 14 was subjected to the optimized metalation conditions
developed for 12a (Table 1, entry 12) followed by TMSCl quench, product 16a was obtained in
3
8
9
7:3 er (Scheme 5). However, as observed with other solvent systems, the high
enantioenrichment was compromised by low yields due to decarbamoylation (with C-to-O TMS
migration). This problem was circumvented by the use of the corresponding N,N-diisopropyl aryl
3
7
O-carbamate 15, whose solubility allowed deprotonation (2.2 equiv s-BuLi/(–)-sparteine, –
3
9
7
8°C, 2 h) to be carried out in hexanes. Under these conditions and after TMSCl quench, the
product 17a was obtained in both high yield and enantioselectivity (Table 3). As in the
deprotonation studies of 5-7 (Scheme 2), use of less base was detrimental to the reaction. For
example, the use of 1.2 equiv of s-BuLi/(–)-sparteine in the MeSSMe quench experiment
afforded 17g in 36% yield and 76:24 er. In previous studies, with few exceptions (in which up to
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20
10,11,33a
2
or ≥2
equiv of alkyllithium/(–)-sparteine were used), a range of 1.1-1.6 equiv of
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
8
alkyllithium/(–)-sparteine had been applied. As shown in Scheme 5, a sequential lateral
metalation reaction consisting of deprotonation of 15 with 1.05 equiv s-BuLi/(–)-sparteine,
quench with 1.05 equiv MeSSMe, followed by 1 equiv s-BuLi/(–)-sparteine resulted in the
formation of 17g in 16% yield and 86:14 er. This suggests that, for this particular system, the total
amount of s-BuLi/(–)-sparteine required to achieve synthetically useful yields must be added at
the beginning of the reaction. Using the 5-TBS N,N-dialkyl aryl O-carbamate 15, a broad scope
of electrophiles was introduced to give products 17b-i in good yields and enantioselectivities,
with one exception (17i) that was not investigated further.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 3. Lateral Metalation-Electrophile Quench Reactions of 15 using s-BuLi/(–)-Sparteine in
Hexane.
+
a
E
E
Product
Yield, %
er
b
TMSCl
TMS
17a
80
85
87
71
91
91
89
90
27
98:2
c
H C=CHCH Br H C=CHCH
2
17b
17c
17d
—
2
2
2
MeOCH Cl
MeOCH2
98:2
98:2
96:4
99:1
97:3
94:6
92:8
2
n-Bu SnCl
n-Bu Sn
3
3
d
Me SnCl
Me Sn
17e
3
3
PhSSPh
MeSSMe
PhSeSePh
PhS
MeS
PhSe
OH
17f
d,e
17g
17h
d
Me SiOOSiMe
17i
3
3
a
b
Yields of isolated products; Use of n-BuLi and s-BuLi in Et O led to a 77% yield, 98:2 er and
2
c
9
6% yield, 94:6 er respectively; Determination of er’s using CSP-HPLC was unsuccessful.
d
e
Performed in Et O; s-BuLi/(–)-sparteine (1.2 equiv) in Et O led to 17g (36% yield, 76:24 er)
2
2
and recovered starting material (41%).
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2
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3
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1
2
The absolute configuration of the major (S)-enantiomer of 17g was determined by single-crystal
X-ray crystallographic analysis of the (–)-camphanoate derivative 19 prepared by reductive
cleavage of the carbamoyl group, followed by esterification using enantiomerically pure (–
)-camphanic acid chloride (Scheme 6, see Experimental Section).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 6. Synthesis and Ortep Plot of 19
H
SMe
H
SMe
1. LiAlH /AlCl
4 3,
Et O, 0°C, 87%
2
2.
O
O
O
TBS
O
TBS
COCl
O
O
N
O
1
7g
1
9
O
9
6:4 er
pyridine, 89%
91:9 dr
Introduction of Remote TMS Protection. Interestingly, and in contrast to previous metalation
studies in the absence of (–)-sparteine which showed that ortho-deprotonation-anionic Fries
28b
rearrangement and lateral deprotonation are competitive, treatment of 20 under the standard
s-BuLi/(–)-sparteine conditions followed by electrophile quench led to 21a (E = MeS) and 21b (E
= Me Sn) in good yields and enantioselectivities with only a moderate solvent effect (Scheme 7)
3
40
and no products resulting from ortho lithiation being observed. The absolute configuration of
the stereogenic center of the major (S)-enantiomer of 21a was determined by single-crystal X-ray
crystallographic analysis (Scheme 7, see Supporting Information).
Scheme 7. TMS as a Remote Protecting Group
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1
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Me Si
3
OCON(i-Pr)2
Me Si
3
OCON(i-Pr)2
1
) s-BuLi/
–)-sparteine
–78°C, 2 h
(
E
20
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2) E+
21a E = MeS
1b E = Me Sn
2
3
E
solvent
yield
er
MeS
MeS
Et O
2
90%
79%
71%
97:3
99:1
94:6
hexanes
2
1a
Me Sn
3
Et O
2
Mechanistic Aspects. In the lithiation-substitution pathway, asymmetry is introduced by free
4c
energy differences in either the formation or reaction of the diastereomeric lithiated species. In
order to distinguish between asymmetric deprotonation and asymmetric substitution, the protocol
4
a,b
established by Beak was followed. Thus compound 6 was subjected to metalation using s-BuLi
in Et O for 2 h and the resulting racemic lithio species rac-9 was treated with (–)-sparteine
2
followed by TMSCl (Scheme 8).
Scheme 8. Lateral Metalation of 6. Origin of the Observed Stereochemistry
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
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3
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3
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5
5
5
5
5
5
5
5
5
6
1
4
1
) (–)-sparteine
Et O, –78°C, 1 h
2
< 51:49 er
SiMe3
2
) TMSCl
–
78°C to r.t., 70%
SiMe3
SiMe3
OCONEt2
OCONEt2
Li
OCONEt2
s-BuLi
Et O, –78°C
1
2a
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
SiMe3
2
2
h
TMSCl
6
rac-9
racemic
–78°C to r.t., 60%
1) s-BuLi/(–)-sparteine
t-BuOMe/toluene 1:3, –78°C, 2 h
2) Bu SnCl
3
–
78°C to r.t., 63%
SiMe3
SiMe3
SiMe
3
MeLi
OCONEt2
SnBu3
OCONEt2
OCONEt
SiMe
3
2
TMEDA
TMSCl
Li
*
–78°C to r.t., 88%
Et O
2
–78°C, 2 h
1
2e
9
12a
8
6:14 er
76:24 er
absolute configuration
assigned by analogy with
compound 11c
The isolated product 12a (E = TMS), obtained in 70% yield, showed <1% ee. A control
experiment was conducted demonstrating the formation of rac-9 in the absence of (–)-sparteine.
Thus, quenching rac-9 with TMSCl afforded rac-12a in 60% yield. In order to establish the
enantiodetermining step, entantioenriched 12e (86:14 er, prepared from 6 using 2.2 equiv of
s-BuLi/(–)-sparteine, t-BuOMe/toluene 1:3, –78°C, 2 h) was subjected to tin-lithium exchange
(MeLi/TMEDA/Et O/–78°C) followed by quench with TMSCl to afford 12a with retention of
2
(
S)-configuration in 88% yield and with 76:24 er. We attribute the erosion in er from 12e to 12a
to be possibly due to the conditions of the tin-lithium exchange reaction (conversion was
4
1
unsuccessful in the absence of TMEDA) as has been previously observed. These observations
demonstrate that racemic lithiated species rac-9 does not lead to enantioinduction upon treatment
with (–)-sparteine and subsequent reaction with TMSCl, and that the enantioenriched lithiated 9
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maintains, in large part, its configurational stability under the reaction conditions. Therefore, the
enantiodiscriminating step in the formation of compounds of type 12 and, by inference, other
carbamates 11, 16, 17, and 21, occurs in the deprotonation and not in the substitution step. These
results are in contrast to the studies of Beak, which reported leaving group-differentiated
enantioselective alkylations in the (–)-sparteine-mediated lateral lithiation of ortho-ethyl N,N-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4
a,4b
diisopropyl benzamides.
For the amide series, it was demonstrated that transfer of
stereochemical information occurs in the post-deprotonation step via dynamic kinetic resolution.
Our results also contrast with those of Beak concerning the enantioselective lateral metalation of
4
b
N-(2-ethylphenyl) pivalamides. In this series, enantioinduction was found to be independent of
the electrophile, but strongly dependant on coordination with the diamine ligand. Transfer of
stereochemical information was also found to occur post-deprotonation, but via dynamic
thermodynamic resolution.
In order to obtain additional information on the stereodifferentiating step, a parallel study
was performed on the N,N-dialkyl aryl O-carbamate 20 (Scheme 9). Attempts to prepare racemic
2
1a by s-BuLi metalation in the absence of a ligand and MeSSMe quench afforded only the
2
8b
lateral carbamoyl migration product 22 as precedented. To overcome this difficulty, rac-21b
was prepared, subjected to tin-lithium exchange (2.2 equiv s-BuLi/(–)-sparteine, Et O, –78°C, 2
2
h) and subsequently quenched with MeSSMe. The product 21a was obtained in 75% yield and
essentially racemic form (53:47 er). In addition to confirming that the extent of organolithium
intermediate formation from tin-lithium exchange and that from direct deprotonation are
30b
essentially identical, these results suggest that the asymmetric substitution reaction appears not
to be the enantiodetermining step for the described reactions of ortho-ethyl N,N-dialkyl aryl O-
carbamates.
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2
2
2
2
2
2
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3
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4
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5
5
5
5
5
5
6
1
6
In a study aimed to obtain confirmation of the results observed on the enantioenriched stannylated
diethyl O-carbamate 12e (Scheme 8), the corresponding tin derivatives 17e and 23b (prepared by
metalation-stannylation of 15 and 20 respectively) were investigated (Scheme 9). Unfortunately,
neither 17e nor 21b were amenable to single-crystal X-ray crystallographic analysis. However,
the assignment of (S)-17e and (S)-21b configuration may be deduced on the basis of their elution
behavior on CSP-HPLC (CHIRALCEL OD column) by comparison with 11c, 19 and 21a whose
absolute configurations were established by X-ray analysis (Figs 1, 2, and 3). Thus, all major
enantiomers of 11c, 19, 17e, 23a, and 21b (as well as similar compounds 11b, 17g and 17i) had
lower retention times and eluted first. Based on this assumption, the transformation of (S)-17e to
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
S)-17g was investigated in order to ascertain the configurational stability of species 23 on the
time scale of the reaction (Scheme 9, Table 4). In this pursuit, enantioenriched (S)-17e (82:18 er)
was subjected to tin-lithium exchange with 1.2 and 2.1 equiv of s-BuLi/(–)-sparteine and with 2.1
equiv of s-BuLi in the absence of the (–)-sparteine ligand, followed by quench with 3.0 equiv of
MeSSMe. Under the generally accepted assumption that tin-lithium exchange proceeds with
43
retention of configuration, (S)-23 is the formed reactive intermediate. The degree of enrichment
of isolated 17g, whose configuration was identical to (S)-17g prepared by the s-BuLi/(–
)
-sparteine/MeSSMe route, varied from 74:26 er (s-BuLi without (–)-sparteine) to 78:22 er (2.1
equiv s-BuLi/(–)-sparteine), indicating that species 23 (and possibly 24) is largely
configurationally stable in the presence as well as in the absence of (–)-sparteine with respect to
4
4
the rate of its reaction with MeSSMe under these conditions.
4b,17g,32b
10
Surprisingly, in contrast to observations by Beak,
and Hoppe, attempts to obtain
the (R)-enantiomer of 17g by tin-lithium exchange in order to offer the desired confirmatory
evidence for these observations, were not successful. The afore-mentioned experiments offer
indirect evidence for the substitution step in the conversion of 17e into 17g proceeding by
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retention of configuration. In the analogous lithiated species of ortho-ethyl benzamides, Beak has
conclusively demonstrated that the retention and inversion pathways are a function of the nature
4
b
and reactivity of the electrophile.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 9. Evidence for the Stereochemical Course of the (–)-Sparteine-Mediated Lateral
Deprotonation Reaction
1
) s-BuLi/(–)-sparteine
Me Si
3
OCON(i-Pr)2
Me Si
3
OCON(i-Pr)2
Et O, –78°C, 2 h
2
SnMe3
2) MeSSMe
5%
SMe
7
rac-21b
21a
5
3:47 er
1) s-BuLi/TMEDA
Et O, –78°C, 2 h
R = TMS
2
) Me SnCl
71%
2
3
R
OCON(i-Pr)2
R
OCON(i-Pr)2
Li•(–)-sparteine
R
OCON(i-Pr)2
s-BuLi
–)-sparteine
Et O, –78°C, 2 h
MeSSMe
(
SMe
*
2
1
5
0
R = TBS
R = TMS
23 R = TBS
24 R = TMS
17g R = TBS
21a R = TMS
2
s-BuLi, no ligand
Et O, 0°C, 2 h, 67%
R = TMS
Me SnCl
3
MeSSMe
2
R
OCON(i-Pr)2
s-BuLi or
s-BuLi/(–)-sparteine
R
OCON(i-Pr)2
Li•(–)-sparteine
SnMe3
Et O, –78°C, 2 h
2
Me Si
3
OH
CON(i-Pr)2
1
2
7e R = TBS
1b R = TMS
23
R = TBS
25 R = TMS
22
absolute configuration assigned
-
-
by analogy to 11c, 19 and 21a
in accordance to the behavior on CSP-HPLC
compared with 11b, 11c, 17g, 17i and 21a
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8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
8
a
Table 4. Configurational Stability of 23: Transformations of 17e to 17g
s-BuLi,
equiv
(–)-sparteine,
equiv
b
er (17e)
Yield, %
er (17g)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
8
2:18
82:18
2:18
1.2
2.1
2.1
1.2
2.1
—
49
67
49
77:23
78:22
74:26
8
a
b
Metalation conditions: –78°C/Et O/2 h; Yields of isolated products.
2
4
5
Based on the elegant studies of Hoffmann concerning the configurational stability of
diastereomeric lithiated species relative to the time scale of reaction with an electrophile (the
Hoffmann Test), Beak developed a modification which avoids the need for enantiomerically
4
b,17g, 19,20,46
enriched reagents (‘poor man’s Hoffmann Test’).
In one variation of this test, the
product stereoselectivities for two reactions are compared: one with an excess and the other with
a deficiency of electrophile. If these two reactions lead to products with different
enantioselectivities, then nonequilibrating diastereomeric complexes undergoing reaction at
different rates are involved. In adapting this test, two separate experiments were performed in
parallel by subjecting 20 to identical lithiation conditions (Scheme 10). The resulting lithiated
species were trapped with MeSSMe under the same conditions, except that one was treated with
an excess and the other with a substoichiometric amount of the electrophile.
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Scheme 10. The ‘Poor Man’s Hoffmann Test’
Me Si
3
OCON(i-Pr)2
SMe
1
) s-BuLi/(–)-sparteine
Me Si
3
OCON(i-Pr)2
Et O, -78°C, 2 h
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
21a
2) MeSSMe, time
3) MeOD
Me Si
3
OCON(i-Pr)2
2
0
D
d-20
yield (21a) er (21a) yield (d-20)
s-BuLi/(–)-sparteine
MeSSMe
time
(
%)
(%)
2
.25 equiv.
.27 equiv.
3 equiv
1 h
54
7
95:5
–
2
0.2 equiv
2 min
63:37
59
Use of 3.0 equiv of MeSSMe led to the isolation of 21a with 95:5. If the benzyllithium species
(23) is configurationally stable on the timescale of the electrophilic quench reaction, this er
reflects the relative population of diastereomeric complexes in solution; on the other hand, if 23 is
configurationally unstable on this timescale, the ee reflects the difference in reaction rates of the
two diastereomeric complexes. When 0.2 equiv of MeSSMe was used, 21a was obtained with
6
3:37 er. The er obtained from quench with this deficient amount of electrophile reflects the
relative rates of reaction of the two diastereomeric complexes. Since the er’s resulting from these
two experiments are significantly different, this suggests that 24 is configurationally stable on the
time scale of the electrophilic trapping experiment - a prerequisite if, as outlined above,
3
2c,41b
asymmetric deprotonation is the enantiodetermining step for the reaction.
As a further
confirmatory experiment, in order to rule out the possibility of further lithiation of 21a, especially
when 0.2 equiv of MeSSMe are used, the reactions were quenched with MeOD and the products
2
were analyzed by H NMR and MS. Aside from the expected formation of d-20 isolated in 59%
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1
1
1
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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5
5
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6
2
0
yield (0.2 equiv of MeSSMe), no indication of further lithiation of 21a (3.0 equiv of MeSSMe)
was detected, as evidenced by a lack of deuterium incorporation.
The observed configurational stability of the laterally lithiated ortho-ethyl N,N-dialkyl aryl
O-carbamates is in contrast to the observations of Beak for both the ortho-ethyl N,N-diisopropyl
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
a,b
benzamides and N-(2-ethylphenyl) pivalamides, where the diastereomeric lithium complexes
were found to be configurationally labile and enantioinduction occurs post-deprotonation via
dynamic resolution processes. Furthermore, our mechanistic studies suggest that configurational
stability in this series is independent of the steric environment surrounding the DMG and the
lithiated center. The lithiated species are configurationally stable regardless of ortho (9) or meta
4
7
(
23, 24) silyl substituion. This is in contrast with the results of Clayden, which demonstrate that
lithiated ortho-ethyl-N,N-diisopropyl benzamides are less configurationally stable than their more
hindered lithiated 2-ethyl-N,N-diisopropyl-1-naphthylamide analogs.
Molecular Modeling
In order to glean further information regarding the stereochemical course of the reaction, a series
of semi-empirical molecular orbital calculations (PM3) were carried out using a gas phase as well
4
8
as a solvated (SMD) model. Results for the reaction path of all substrates examined (5, 6, 20)
are similar, and thus only one (20) is discussed in detail using the solvated model. A
conformational search revealed that three possible low-energy geometries (A, B, C) for the
substrate are adopted. Introduction of the s-BuLi/(–)-sparteine complex results in coordination of
lithium to the carbamoyl carbonyl group in each case. Subsequent prochiral hydrogen
deprotonation may occur for the adducts of conformations A and B (Scheme 11) but not for
conformation C since the hydrogens are oriented away from the coordinated alkyllithium. Thus
only the pathways for A and B are considered further.
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1
For conformation A, the calculations show that abstraction of the pro-(S) hydrogen
occurs, whereas for B the pro-(R) hydrogen is abstracted. This enantioselective deprotonation was
found experimentally by tin-lithium exchange studies to be responsible for the observed
enantioselectivity for ortho-TMS substrate 6 (Scheme 8) and for meta-TMS substrate 15 (Scheme
9). Comparison of the transition state models reveals that TS1(A) is more stable than TS1(B) by
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
1.0 kJ/mol in the solvated state (Scheme 11), which is in qualitative agreement with the
4
9
experimentally determined ee. Complete transfer of the proton results in the formation of
intermediates Int(A) and Int(B).
Introduction of MeSSMe as an electrophile results in reaction with the lithiated
intermediates. Based on electrostatic potentials and the location of the highest density LUMO of
the lithiated intermediates Int(A) and Int(B), the electrophile is found to approach from the top
face for both TS2(A) and TS2(B), leading to insertion into the C-Li bond. The outcome is
retention of configuration in the formation of complexes C3(A) and C3(B). The results of the
calculated kinetically favored formation of intermediate Int(A) over Int(B) and the energetically
favorable insertion of the electrophile with retention of stereochemistry are qualitatively in
agreement with our experimental results for the stereochemical outcome in the conversion of 20
to 21a.
Limitations in the precision of these calculations prevents us from making quantitative
comparisons between the enantioselectivities observed for different substrates, i.e. ortho- vs
meta-TMS, N,N-diethyl- vs N,N-diisopropyl aryl O-carbamates. However, calculations are
48
qualitatively in agreement with the observed er’s for other substrates.
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8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
2
Scheme 11. Solvated Model Reaction Pathway for the Conversion of 20 to 21a
ꢀE
sol
(kJ/mol)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
TS1(B)
0.3
TS1(A)
TS2(A)
TS1(B)
9
TS2(B)
7
9.3
TS2(A)
2.8
3
Int(A)
TS2(B)
9.4
B
2
B
A
0.0
Int(A)
11.0
-
TS1(A)
Int(B)
-12.3
C3(B)
C3(B)
65.3
-
C3(A)
75.3
-
Int(B)
C3(A)
A
Subsequent Functionalizations: N,N-dialkyl aryl O-Carbamate Hydrolysis and Desilylation.
In order to convert N,N-dialkyl aryl O-carbamates into synthetically useful phenols following
benzylic functionalization, several methods were tested. Diisopropyl O-carbamates show
2
5a
considerable stability towards hydrolysis. After considerable experimentation, we were pleased
to observe that reductive cleavage of 17g using LiAlH (1.2 equiv)/AlCl (1.6 equiv) in Et O
4
3
2
(
0°C ꢀ rt, 2-3 h) was successful and afforded the corresponding phenol. The configuration of
1
7g was preserved to a large extent during its conversion into the camphanoate derivative 19. In
contrast, when compound 21a (E = MeS) was subjected to these conditions, partial racemization
50
was observed.
Selected examples of desilylation are shown in Scheme 12. The TMS-substituted 12b was
desilylated to 25 using TBAF (6 equiv) in 62% yield without erosion of optical activity and the
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3
TBS-substituted 17f (99:1 er) was converted into 26 (98:2 er) in neat TFA at room temperature in
78% yield.
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 12. Subsequent Reactions: Deprotection.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
SiMe3
OCONEt2
OCONEt2
9
TBAF
THF, r.t.
2%
9
6
12b
25
8
3:17 er
83:17 er
TBS
OCON(i-Pr)2
OCON(i-Pr)2
TFA, r.t.
8%
SPh
SPh
7
1
7f
26
9
9:1 er
98:2 er
absolute configurations assigned
by analogy with 11c, 19 and 21a
Conclusions
A general synthesis of enantioenriched, laterally substituted ortho-ethyl-N,N-dialkyl aryl O-
carbamates using (–)-sparteine mediated, directed lateral metalation strategy was demonstrated
applying a reliable, preparatively simple, protocol. Thus, optically active products 11-13, 16, 17
and 21 were obtained in high yields and enantioselectivities from the corresponding ortho-silyl or
functionalized 5-7 and meta-silyl 14, 15 and 20 O-carbamates. N,N-Diisopropyl aryl O-
carbamates proved to be superior to N,N-diethyl aryl O-carbamates in terms of minimizing side
reactions, and s-BuLi was found to be the optimal reagent for deprotonation. For preparative
reactions, 2.2 equiv of s-BuLi/(–)-sparteine complex and up to 3 equiv of the electrophile in a
variety of solvents (Et O, t-BuOMe, (i-Pr) O, hexanes, toluene or t-BuOMe/toluene 1:3) at –
2
2
78°C) gave satisfactory results. Sterically demanding ortho- substituted N,N-dialkyl aryl O-
carbamates 5-7 gave products 11-13 with low to moderate enantioinduction. meta-Substituted
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silyl derivative 15 afforded product 17g with higher enantioinduction than in the conversion of
the corresponding ortho derivative 7 to 13a, suggesting a concept of remote silicon protection
which may be of more general synthetic value. The identical absolute configuration of the major
enantiomers at the newly formed benzylic stereogenic center, demonstrating a consistent
stereochemical course for the reaction, was determined for three sulfur-containing substrates 11c,
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7
8
9
0
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2
3
4
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6
7
8
9
0
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3
4
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6
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9
0
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3
4
5
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8
9
0
1
2
3
4
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9
0
1
9 and 21a. A mechanistic investigation of the reaction starting from 6 and 15 revealed that the
enantioinduction occurs in the deprotonation step rather than in the substitution step to give
products 20a and 17g with retention of configuration with respect to their lithiated intermediates.
Benzyllithium species 9 and 23, generated from the corresponding tin derivatives, were observed
to be largely configurationally stable on the time scale of the reaction in the presence or absence
of (–)-sparteine. The configurational stability of the benzyllithium species 24 prepared by direct
lithiation was confirmed by a modified Hoffmann test. The results of semiempirical molecular
orbital calculations (PM3/SMD) support the experimental observations concerning the retentive
stereochemical course of the reaction in which enantioinduction occurs in the deprotonation
4b
step. Desilylation of 12b and 17f was performed using TBAF or TFA to give products 25 and
2
6, and the decarbamoylation of 17g using LiAlH /AlCl , followed by treatment with (-)-
4 3
camphenic acid chloride was achieved to afford the corresponding ester 19. The overall results
are expected to be valuable in constructing chiral benzyl derivatives which, by further
5
1
manipulation, may be adaptable to application in biomolecule and natural product synthesis.
Experimental Section
General Methods: Solvents and reagents were used without further purification unless otherwise
indicated. Diethyl ether (Et O), tert-butyl methyl ether (t-BuOMe), toluene and tetrahydrofuran
2
(
THF) were distilled from sodium/benzophenone under an Ar-atmosphere. Hexanes was distilled
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2
5
from CaH under an Ar-atmosphere. TMEDA and (–)-sparteine were distilled from CaH under
2
2
an Ar-atmosphere. Solutions of n-BuLi in hexanes, s-BuLi in cyclohexane and t-BuLi in pentane
5
2
were titrated periodically according to the method of Watson and Eastham. A –78°C bath refers
to a mixture of dry ice in acetone, a 0°C bath refers to an ice/water slush.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
H NMR spectra were recorded on 200, 250, 300 or 400 spectrometers using tetramethylsilane
(TMS) as internal standard. Chemical shifts are reported in ppm relative to TMS. For peak
multiplicities, the following abbreviations are used: s, singlet; d, doublet; t, triplet; q, quartet; dd,
1
3
doublet of a doublet; m, multiplet; br., broad. C NMR spectra were proton decoupled and
recorded on 200, 250 and 300 spectrometers at 50, 62.5 or 75 MHz using the respective solvent
as internal standard. IR spectra were recorded on an infrared spectrophotometer as KBr disc or
thin film (NaCl plates). Electron impact mass spectra (EI MS) were performed (4kV, 35eV,
2
20°C) on triple quadrupole mass spectrometer instruments. Melting points are not corrected.
Chiral HPLC analyses using chiral columns were performed at room temperature at 254 nm.
Enantiomeric purity assays using chiral HPLC columns were completed with both racemic and
enantioenriched materials and repeated at least once in order to ensure accuracy of the method
used. Flash chromatography (FC) was performed with silica gel (230-400 mesh, 60 Å). Analytical
thin layer chromatography was performed on silica gel UV254 plates. If microanalyses are not
1
13
reported, the purities of the compounds were determined to be >90% by H NMR and C NMR
spectra, and the molecular ion was confirmed by high resolution mass spectrometry (HR MS). All
reported yields are isolated yields unless specified otherwise.
Preparation of 2-Ethyl-6-methoxyphenyl diethylcarbamate (5).
2-methoxyphenyl diethylcarbamate: A mixture of 2-methoxyphenol (10.0 g, 80.55 mmol),
diethylcarbamoyl chloride (11.23 mL, 88.63 mmol) and K CO (12.25 g, 88.64 mmol) in CH CN
2
3
3
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9
1
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1
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2
2
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2
2
2
2
2
2
3
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3
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3
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4
4
4
4
4
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5
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5
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5
5
5
5
5
5
6
2
6
(
250 mL) was heated at reflux for 14 h. Remaining K CO was removed by filtration. The organic
2 3
phase was concentrated in vacuo and the residue was dissolved in Et O (200 mL), washed with
2
1
0% aq. KOH and H O. The organic layer was dried over anhydrous MgSO , subjected to
2
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
filtration and concentrated in vacuo. FC (hexanes/Et O 2:1) provided 17.95 g (99%) of 2-
2
1
methoxyphenyl diethylcarbamate as colorless oil: b.p. 110-115°C (0.05 mm Hg); H NMR (250
MHz, CDCl ): δ 7.17-6.90 (m, 4H), 3.82 (s, 3H), 3.42 (q, J = 7.4 Hz, 4H), 1.23 (t, J = 7.6 Hz,
3
1
3
6
H); C NMR (CDCl ): δ 154.1, 151.7, 140.6, 126.0, 123.3, 120.6, 112.3, 55.8, 42.2, 41.9, 13.9,
3
–
1
1
3.3; IR υmax (film): 2974, 1722, 1606, 1503, 1419, 1260, 1203, 1155, 1113 cm ; EI MS m/z:
+
2
23 ([M] , 3), 109 (16), 100 (100); Anal. calc. for C H NO ; C, 64.55; H, 7.67; N, 6.27; found:
12 17
3
C, 64.46; H, 7.78; N, 6.16.
2
1
–
-Ethyl-6-methoxyphenyl diethylcarbamate (5): A solution of s-BuLi (41.0 mL, 53.7 mmol,
.31M solution in cyclohexane) and TMEDA (8.1 mL, 53.7 mmol) in THF (300 mL) was kept at
78°C for 5 min, then a solution of 2-methoxyphenyl diethylcarbamate (10.0 g, 44.79 mmol) in
THF (50 mL) was added dropwise via cannula at –78°C, and the resulting yellow solution was
stirred at –78°C for 1 h. Iodoethane (10.8 mL, 134.4 mmol) was added dropwise and the resulting
solution was allowed to warm to room temperature overnight. The mixture was quenched with
saturated aq. NH Cl solution and extracted with Et O. The organic extracts were washed with
4
2
H O and brine, dried over anhydrous MgSO , subjected to filtration and concentrated in vacuo.
2
4
1
FC (hexanes/Et O 1:1) afforded 8.96 g (80%) of 5 as pale orange viscous liquid. H NMR (300
2
MHz, CDCl ): δ 7.11-7.06, 6.83-6.77 (2 t-like m, 3H), 3.81 (s, 3H), 3.49-3.39 (m, 4H), 2.58 (q, J
3
1
3
=
7.6 Hz, 2H), 1.3-1.2 (m, 6H), 1.19 (t, J = 7.6 Hz, 3H); C NMR (CDCl ) δ 153.7, 151.7, 138.6,
3
1
37.6, 125.5, 120.6, 109.7, 55.7, 42.0, 41.8, 23.1, 14.2, 13.9, 13.3; IR υmax (film): 2971, 1721,
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–1
+
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475, 1419, 1276, 1195, 1156, 1087 cm ; EI MS m/z: 251 ([M] , 15), 152 (20), 137 (71), 135
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
22); HR MS (EI) calc. for C H NO : 251.1521; found: 251.1510.
14 21
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
General Procedure A for lithiation/electrophile quench of 2-Ethyl-6-methoxyphenyl
diethylcarbamate (5): To a stirred solution of (–)-sparteine in anhydrous solvent at –78°C
s-BuLi was added and stirring was continued at –78°C for 15 min. A solution of 5 in anhydrous
solvent was added dropwise and the resulting yellow solution (suspension) was stirred at –78°C.
The electrophile was added and the resulting colorless suspension was stirred at –78°C for 1 h
and then allowed to warm to room temperature. The mixture was quenched with saturated aq.
NH Cl solution, extracted with Et O and the combined organic extract was washed with H O
4
2
2
and brine, dried over anhydrous MgSO , subjected to filtration and concentrated in vacuo.
4
Purification by FC followed. The molar ratios of reagents and quantities of solvents are specified
for TMSCl quench in the following procedure. The different solvents that have been used, yields
and enantiomeric ratios are specified in Table 1.
2
-Methoxy-6-[(1S)-1-(trimethylsilyl)ethyl]phenyl diethylcarbamate (11a): According to
General Procedure A: A solution of 5 (293 mg, 1.16 mmol) in i-Pr O (5 mL) was added to a
2
mixture of s-BuLi (2.14 mL, 2.57 mmol, 1.20M solution in cyclohexane) and (–)-sparteine (0.59
mL, 2.57 mmol) in i-Pr O (10 mL) at –78°C. After addition of trimethylsilyl chloride (0.44 mL,
2
3.47 mmol) at –78°C, the mixture was worked up and purified by FC (hexanes/Et O 1:1) to give
2
2
5
1
1
91 mg (50%) of 11a as colorless oil: [α] = +26.3 (EtOAc, c = 1.60); H NMR (250 MHz,
D
CDCl ): δ 7.05 (t, J = 8.0 Hz, 1H), 6.68 (m, 2H), 3.77 (s, 3H), 3.39 (b, 4H), 2.38 (q, J = 7.5 Hz,
3
1
3
1
H), 1.30 (d, J = 7.6 Hz, 3H), 1.24 (b, 6H), –0.06 (s, 9H); C NMR (CDCl ): δ 153.5, 151.5,
3
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39.6, 137.6, 124.9, 118.9, 108.0, 55.6, 41.9, 41.7, 21.6, 14.7, 13.9, 13.1, –10.2; IR υmax (film):
–
1
+
2957, 1722, 1469, 1419, 1270, 1159, 844 cm ; EI MS m/z: 323 ([M] , 12), 308 (14), 251 (19),
2
23 (49), 174 (11), 135 (4), 100 (100), 72 (90); HR MS (EI) calc. for C H NO Si: 324.19949;
17 30 3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
found: 324.19961.
The enantiomeric ratio was determined to be 96:4 ((S,S)-WHELK-01 column, 1% 2-propanol in
hexanes, 1.0 mL/min).
2-Methoxy-6-[(1S)-1-(methylsulfanyl)ethyl]phenyl diethylcarbamate (11b): According to
General Procedure A: A solution of 5 (364.9 mg, 1.45 mmol) in Et O (5 mL) was added to a
2
mixture of s-BuLi (2.54 mL, 3.63 mmol, 1.43M solution in cyclohexane) and (–)-sparteine (851
mg, 3.63 mmol) in Et O (15 mL) at –78°C. After addition of a solution of dimethyl disulfide (479
2
mg, 5.1 mmol) in Et O (3 mL) at –78°C, the mixture was worked up and purified by FC
2
25
(hexanes/EtOAc 6:1) to give 198 mg (46%) of 11b as yellowish oil: [α] D = –0.19 (EtOAc, c =
1
0
.5); H NMR (300 MHz, CDCl ): δ 7.19-7.11 (m, 2H), 6.82-6.79 (m, 1H), 4.15 (q, J = 7.1 Hz,
3
1H), 3.81 (s, 3H), 3.49-3.37 (m, 4H), 1.92 (s, 3H), 1.52 (d, J = 7.1 Hz, 3H), 1.31-1.18 (m, 6H);
13
C NMR (CDCl ): δ 153.5, 151.4, 138.4, 137.3, 125.8, 118.9, 110.2, 55.8, 42.1, 41.9, 38.4, 21.5,
3
14.4, 14.1, 13.2; IR υmax (film): 2972, 1723, 1587, 1475, 1419, 1274, 1155, 1094, 1049, 958, 781
–
1
+
cm ; EI MS m/z: 297 ([M] , 8), 250 (100), 150 (27); HR MS (EI) calc. for C H NO S:
1
5
23
3
2
97.1399; found: 297.1380.
The enantiomeric ratio was determined to be 94:6 (CHIRALCEL OD column, hexanes/EtOAc/2-
propanol 92:7:1, 1.0 mL/min).
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The Journal of Organic Chemistry
1
2
3
2
9
2
-Methoxy-6-[(1S)-1-(methylsulfonyl)ethyl]phenyl diethylcarbamate (11c): To a solution of
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
1b (104 mg, 0.35 mmol, 85% ee) in CH Cl (2 mL) was added a solution of m-CPBA (ca. 55%,
2
2
9
90 mg, 3.16 mmol) in CH Cl (5 mL) at room temperature. After 6 h, the mixture was diluted
2 2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
with Et O and washed with saturated aq. Na S O solution, NaHCO solution and brine. The
2
2
2
8
3
organic layer was dried over anhydrous MgSO and concentrated in vacuo. FC (hexanes/EtOAc
4
25
1
:1) afforded 105.9 mg (92%) of 11c as colorless solid: m.p. 106-107°C (from oil); [α] D = +0.02
1
(EtOAc, c = 0.5); H NMR (300 MHz, CDCl ): δ 7.30-7.20 (m, 2H), 6.97-6.93, (m, 1H), 4.54 (q,
3
J = 7.1 Hz, 1H), 3.83 (s, 3H), 3.49 (q, J = 7.1 Hz, 2H), 3.38 (q, J = 7.1 Hz, 2H), 2.69 (s, 3H), 1.72
1
3
(d, J = 7.1 Hz, 3H), 1.30 (t, J = 7.1 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H); C NMR (CDCl ): δ 153.3,
3
1
51.6, 139.0, 129.3, 126.4, 119.4, 112.2, 56.6, 55.8, 42.4, 42.1, 38.8, 14.0, 13.1, 13.0; IR υmax
–
1
(KBr): 2978, 2931, 1728, 1422, 1297, 1279, 1179, 1142, 1042, 958, 790 cm ; CI MS (isobutane)
+
m/z: 330 ([M+H] , 23), 250 (43), 150 (100), 137 (15), 110 (30); HR MS (EI) calc. for
C H NO S: 329.1297; found: 329.1282.
1
5
23
5
The enantiomeric ratio was determined to be 93:7 (CHIRALCEL OD column, hexanes/2-
propanol 90:10, 0.9 mL/min).
Preparation of 2-Ethyl-6-(trimethylsilyl)phenyl diethylcarbamate (6)
2
-ethylphenyl diethylcarbamate: A mixture of 2-ethylphenol (10.0 g, 81.85 mmol),
diethylcarbamoyl chloride (10.40 mL, 82.07 mmol) and K CO (15.0 g, 108.53 mmol) in CH CN
2
3
3
(250 mL) was heated at reflux for 24 h. Remaining K CO was removed by subjecting to
2 3
filtration. The organic phase was concentrated in vacuo and the residue was dissolved in CHCl3
200 mL), washed with 10% aq. KOH and H O. The organic layer was dried over anhydrous
(
2
MgSO , subjected to filtration and concentrated in vacuo. FC (hexanes/EtOAc 9:1) provided
4
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