Simple and efficient asymmetric α-alkylation and α,α- bisalkylation of acyclic ketones by using chiral N-amino cyclic carbamate hydrazones

Article abstract of DOI:10.1002/anie.200800848

(Chemical Equation Presented) Distinguishing left from right: In the title reactions, chiral N-amino cyclic carbamates (ACCs) substantially diminish the drawbacks associated with the use of chiral dialkyl hydrazines, yet provide excellent stereoselectivity and high yields. In addition, ACCs exhibit a unique directing effect that overrides the inherent selectivity of lithium diisopropylamide (LDA) and enables the asymmetric α,α-bisalkylation of ketones (see scheme).

Full text of DOI:10.1002/anie.200800848

Angewandte
Chemie
DOI: 10.1002/anie.200800848
Asymmetric Synthesis
Simple and Efficient Asymmetric a-Alkylation and a,a-Bisalkylation
of Acyclic Ketones by Using Chiral N-Amino Cyclic Carbamate
Hydrazones
Daniel Lim and Don M. Coltart*
Ketone a-alkylation is fundamental to organic synthesis.
Remarkably, however, only one effective asymmetric version
of this transformation applicable to acyclic systems is
available.[1–3] Introduced over 25 years ago, this method is
based on the alkylation of metalated SAMP/RAMP hydra-
zones, and has enabled numerous total syntheses.[1] Unfortu-
nately, its further development has been impeded as a result
of certain inherent limitations. For instance, the dialkyl
hydrazones used are only weakly acidic, so azaenolate
formation requires exposure to lithium diisopropylamide
(LDA) for 2–10 h.[1a] Alkylation must then be conducted at an
extremely low temperature (ꢀ110 to ꢀ788C),[1a] making
large-scale applications impractical. Moreover, removal of
the costly auxiliary under recommended[1a] conditions (ozo-
nolysis or quaternization/hydrolysis) limits functional group
compatibility. The auxiliary itself is liberated in an altered
form that hinders recycling.[4] Given these limitations, it is
apparent that asymmetric a-alkylation of ketones remains an
unsolved problem. Herein, we report a substantial advance in
this field through the development of chiral N-amino cyclic
carbamates (ACCs). These auxiliaries significantly diminish
the drawbacks associated with the use of chiral dialkyl
hydrazines, yet still provide excellent stereoselectivity. In
addition, the auxiliaries exhibit a unique directing effect that
overrides the inherent selectivity of LDA, thus enabling the
asymmetric a,a-bisalkylation of ketones, a previously unat-
tainable transformation.
conditions, and are rapidly hydrolyzed under similarly mild
conditions, making them excellent candidates for auxiliary-
based synthetic methods. We anticipated that the enhanced
acidity of these activated hydrazones would enable rapid
metalation over a range of temperatures. Moreover, the
substantial electron density imparted to the electron with-
drawing group in the derived azaenolates (2) should lead to
tight metal cation binding, in a manner analogous to, for
example, chelation of hydroxamate anions. In the context of
asymmetric transformations, this could potentially bring high
facial selectivity during alkylation, even at temperatures well
above ꢀ110 to ꢀ788C, as required of SAMP/RAMP systems.
Collectively, these factors suggested that chiral hydrazines
substituted with a conjugated electron-withdrawing group
could provide the basis of a simple method for asymmetric
ketone a-alkylation.
We focused our initial studies along these lines on the
easily accessible ACCs.[5] Thus, 3 was prepared by amination
of the corresponding oxazolidinone and was then condensed
with 3-pentanone to give 8 (Table 1). This activated hydra-
Table 1: Asymmetric allylation of ACC hydrazones.[a]
Hydrazones possessing an electron withdrawing group (1,
Scheme 1), which we term activated hydrazones, are readily
formed from the corresponding substituted hydrazines (e.g.,
hydrazides, sulfonyl hydrazides, etc.) and ketones under mild
Entry
ACC
Hydrazone
Allylated
hydrazone
Yield [%]
(R)-7/(S)-7
1
2
3
4
3
5
4
6
8
9
10
11
12
13
14
15
90
82
93
96
76:24
86:14
91:9
96:4
[a] Ts=toluenesulfonyl.
zone 8 was readily deprotonated with LDA at ꢀ788C and
allylated in excellent yield (90%). The auxiliary was also
easily removed and recovered quantitatively, giving (R)- and
(S)-7 in a 76:24 ratio. The analogous sequence with ACC 5 led
to a better asymmetric induction (86:14). Suspecting that an
increase in steric bulk near the amino function would result in
a better selectivity, we examined ACC 4. Indeed, alkylation of
the derived hydrazone 10 gave (R)- and (S)-7 in a ratio of 91:9.
The enantiomeric ratio was further improved to 96:4 using the
more conformationally rigid ACC 6.
Scheme 1. Activated hydrazone deprotonation (1!2) and N-amino
cyclic carbamates (3–6). Bn=benzyl.
[*] D. Lim, Prof. D. M. Coltart
Department of Chemistry
Duke University, Durham, NC 27708 (USA)
Fax : (+1)919-660-1605
E-mail: don.coltart@duke.edu
Allylation by using auxiliaries 4 and 6 was studied under a
variety of conditions (Table 2). Of the bases evaluated, LDA
Angew. Chem. Int. Ed. 2008, 47, 5207 –5210
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5207

Communications
Table 2: Effect of reaction conditions on stereoselectivity.
Entry Hydrazone Base
Solvent
T [8C] (R)-7/(S)-7
ꢀ78 to RT 96:4
1
2
11
11
11
11
11
11
11
11
11
11
11
10
10
10
10
10
10
LDA
LDA
THF
Et2O
toluene
THF
ꢀ78 to RT 96:4
ꢀ78 to RT 96:4
ꢀ78 to RT 87:13
ꢀ78 to RT 82:18
ꢀ78 to RT 82:18
ꢀ110 to RT 96:4
ꢀ60 to RT 96:4
ꢀ40 to RT 96:4
ꢀ20 to RT 91:9
0 to RT 90:10
3
4
5
6
LDA
LiHMDS[a]
NaHMDS[a] THF
KHMDS[a]
LDA
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
7
8
LDA
9
LDA
10
11
12
13
14
15
16
17
LDA
LDA
LDA
LDA
LDA
LDA
LDA
LDA
ꢀ110 to RT 91:9
ꢀ78 to RT 91:9
ꢀ60 to RT 90:10
ꢀ40 to RT 91:9
ꢀ20 to RT 85:15
0 to RT 86:14
[a] HDMS=hexamethyldisilazide.
Figure 1. Structures of 23 (top) and 26 (bottom) in the solid state.
C white, Br light gray, O gray, N black.
gave the highest stereoselectivity and showed no solvent
dependence. The asymmetric induction proved largely inde-
pendent of temperature; the same high selectivity was
obtained when the alkylation was conducted up to ꢀ408C,
with only a slight decrease at temperatures up to 08C.
The scope of the reaction was examined with ACC 4 and 6
(Table 3). Excellent yield and stereoselectivity resulted for
each alkyl halide examined, including a secondary alkyl
iodide (Table 3, entry 6). ACC 6 consistently outperformed 4
in terms of asymmetric induction, giving results comparable
with literature reports, yet with considerably improved yields
of isolated products.[6] Alkylation by using ACCs is also very
easy to carry out: hydrazone formation and cleavage are
straightforward and efficient, with no damage or loss of the
auxiliary, and the azaenolate is readily formed and alkylated
at temperatures up to 08C. Significantly, this simple method
engenders the possibility of large-scale asymmetric a-alkyla-
tion of ketones. In a preliminary test, we carried out the
allylation using 7.002 g of 11, which was more than a 100-fold
increase over our initial experiments. Exposure of 11 to LDA
for 45 min at ꢀ408C, followed by addition of allyl bromide
and stirring for 45 min, gave 15 in 98% yield. Hydrolysis with
p-TsOH·H2O in acetone (15 min) afforded ketone 7 in 94%
yield with an unchanged enantiomeric ratio (96:4), along with
acetone-derived hydrazone 38 in 98% yield. After treatment
of 38 with HONH2·HCl in THF/H2O, the ACC auxiliary 6 was
recovered in 95% yield.
Crystal structures of the major diastereomer of 23 and 26
(Figure 1) showed that alkylation occurs syn to the auxiliary,
relative to the C–N double bond, indicating that the
azaenolate intermediate likely has
the Z configuration about this
Table 3: Asymmetric alkylation by using ACC 4 and 6.
bond (ZCN). Furthermore, alkyla-
tion in each case (11!23; 18!26)
provided the same sense of chir-
ality at the newly formed stereo-
genic center, implying that, like
cyclic compound 18, the acyclic
systems react through the azaeno-
late with E configuration at the C–
C bond (ECC).
Entry
R
R1
ACC
Hydra-
zone
R3X
Alkylated
hydrazone
Yield
[%]
Ketone
b/a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Et
Et
Et
Et
Et
Et
Et
Ph
iPr
Me
Me
Me
Me
Me
Me
Me
Me
Me
6
6
6
6
6
6
6
6
6
6
4
4
4
4
11
11
11
11
11
11
11
16
17
18
10
10
10
10
allylBr
BnBr
EtI
PrI
PrOTs
iPrI
15
19
20
21
21
22
23
24
25
26
14
27
28
29
96
99
92
89
76
77
93
91
88
91
93
98
83
77
7
96:4
96:4
97:3
96:4
85:15
94:6
96:4
96:4
98:2
82:18
91:9
92:8
90:10
92:8
30
31
32
32
33
34
35
36
37
7
The regioselectivity of the alky-
lation was consistent with a direct-
ing effect in the deprotonation
step, which could provide a con-
venient and general means of over-
riding the inherent selectivity of
LDA. Moreover, this would make
the direct asymmetric synthesis of
optically enriched a,a-disubsti-
tuted ketones possible for the first
time. To test this idea, 38 was
subjected to allylation giving 39
ArCH2Br[a]
allylBr
allylBr
allylBr
allylBr
BnBr
EtI
-(CH2)4-
Et
Et
Et
Et
Me
Me
Me
Me
30
31
32
PrI
[a] Ar=4-BrC6H4.
5208 www.angewandte.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 5207 –5210

Angewandte
Chemie
regioselectively in 94% yield as a single double-bond
diastereomer. Alkylation of 39 also proceeded regioselec-
tively to give the a,a- and the a,a’-bisalkylation products 41
(97:3 diastereomeric ratio; major shown) and 40, respectively,
in a 92:8 ratio, thus demonstrating the concept of directed
deprotonation (Scheme 2). In contrast, LDA-mediated bisal-
kylation of ketones,[7] imines,[2] and dialkyl hydrazones[1] gives
a,a’-bisalkylation products. This appears to be the first
instance of not only directed deprotonation in azaenolate
formation through a neutral coordinating element,[8] but also
asymmetric a,a-bisalkylation of a ketone.
from ketones with near quantitative recovery. Furthermore,
deprotonation is rapid, and alkylation does not require
extremely low temperature, yet proceeds with excellent
stereoselectivity and substantially higher yields. Collectively,
these traits render the prospect of large-scale asymmetric
ketone a-alkylation, which has previously not been possible.
Furthermore, the ACC auxiliaries exhibit a unique directing
effect that overrides the inherent selectivity of LDA, enabling
for the first time the asymmetric a,a-bisalkylation of ketones.
Further studies of this directing effect and the mechanistic
details, scope, and synthetic utility of this reaction are
underway.
Experimental Section
General procedure for oxazolidinone N-amination: nBuLi (2.5m in
hexanes, 11.4 mL, 28.6 mmol) was added dropwise over ca. 10 min to
a stirred and cooled (ꢀ788C) suspension of 7,7-dimethylnorbornane-
(1S,2R)-oxazolidinone[9] (4.321 g, 23.9 mmol) in THF (350 mL) under
an argon atmosphere. Ph2P(O)ONH2 (6.674 g, 28.6 mmol) was then
added and the mixture was removed from the cold bath, stirred for
12 h, filtered, and evaporated under reduced pressure to give a yellow
solid. Flash chromatography over silica gel using EtOAc/hexanes
(25:75) gave 6 (4.407 g, 94%) as a white solid. 1H NMR (CDCl3,
400 MHz): d = 4.16 (dd, J = 8.2, 4.1 Hz, 1H), 3.91 (s, 2H), 2.30–2.10
(m, 2H), 2.05–1.70 (m, 3H), 1.36–1.24 (m, 1H), 1.18 (s, 3H), 1.0 ppm
(s, 3H); 13C NMR (CDCl3, 100 MHz): d = 160.2, 83.2, 72.1, 47.3, 42.7,
35.1, 25.8, 25.4, 20.7, 19.5 ppm; ESI-MS: m/z [M + H]+ calcd for
C10H17N2O2: 197.26, found 197.1.
General procedure for hydrazone formation: p-TsOH·H2O
(0.96 g, 5.05 mmol) was added to a stirred solution of 6 (6.144 g,
31.31 mmol) and 3-pentanone (3.95 mL, 37.28 mmol) in CH2Cl2
(300 mL) under an argon atmosphere). The mixture was refluxed
for 18 h, cooled to room temperature, and partitioned between
CH2Cl2 and saturated aqueous NaHCO3. The organic phase was
washed with brine, dried over MgSO4, filtered, and evaporated under
reduced pressure to give a yellow oil. Flash chromatography over
silica gel using EtOAc/hexanes (10:90) gave 11 (7.645 g, 92%) as a
white solid. 1H NMR (CDCl3, 400 MHz): d = 4.25 (dd, J = 8.2, 4.1 Hz,
1H), 2.50–2.20 (m, 4H), 2.10–1.80 (m, 4H), 1.76 (t, J = 4.4 Hz, 1H),
1.32–1.24 (m, 1H), 1.23 (s, 3H), 1.15 (s, 3H), 1.13 (t, J = 7.4 Hz, 3H),
1.07 ppm (t, J = 7.4 Hz, 3H); 13C NMR (CDCl3, 100 MHz): d = 181.6,
155.3, 82.9, 73.3, 47.9, 42.9, 35.5, 29.1, 26.6, 25.8, 21.4, 19.3, 10.7,
10.5 ppm; ESI-MS: m/z [M + H]+ calcd for C15H25N2O2: 265.37, found
265.1.
Scheme 2. Regioselective asymmetric a,a-bisalkylation of 38.
A stereochemical model consistent with the above
observations is shown in Scheme 3. Deprotonation of 42
gives azaenolate 43 that is then alkylated from its less-
hindered face to form 44. The ECC configuration of 43
originates from minimization of steric interactions between
the syn b-methyl group and the auxiliary in 42, and directed
deprotonation through coordination of the carbonyl oxygen
and LDA sets the ZCN configuration. In this form, the bottom
(re) face of the azaenolate is blocked, causing the electrophile
to approach from the top (si) face.
In conclusion, we have developed a convenient method
for asymmetric a-alkylation and a,a-bisalkylation of ketones
by using ACC chiral auxiliaries. In contrast to other methods,
the auxiliaries are both easily introduced into and removed
General procedure for hydrazone alkylation: nBuLi (2.5m in
hexanes, 11.65 mL, 29.13 mmol) was added dropwise over ca. 2 min to
a stirred and cooled (ꢀ788C) solution of diisopropylamine (4.45 mL,
31.77 mmol) in THF (60 mL) under an argon atmosphere. The
mixture was transferred to an ice bath, stirred for 30 min, and then
cooled to ꢀ408C. A solution of 11 (7.002 g, 26.48 mmol) in THF
(260 mL) was added by cannula, with additional THF (2 ” 2.0 mL) as
a rinse, and the mixture was stirred for 45 min. Allyl bromide
(2.52 mL, 29.13 mmol) was then added and stirring was continued for
5 min. The cold bath was removed and the mixture was stirred for an
additional 40 min and then partitioned between Et2O and H2O. The
aqueous phase was extracted with Et2O (2 ” 500 mL), and the
combined organic extracts were washed with brine, dried over
MgSO4, filtered, and evaporated under reduced pressure to give a
yellow oil. Flash chromatography over silica gel using EtOAc/hexanes
(10:90) gave 15 (7.899 g, 98%) as a light-yellow oil. 1H NMR (CDCl3,
400 MHz): d = 5.90–5.70 (m, 1H), 5.18–4.94 (m, 2H), 4.25 (dd, J = 8.1,
4.1 Hz, 1H), 3.18–3.04 (m, 1H), 2.50–2.24 (m, 4H), 2.14–1.80 (m, 4H),
1.76 (t, J = 4.4 Hz, 1H), 1.26–1.32 (m, 2H), 1.23 (s, 3H), 1.16 (s, 3H),
1.13 (t, J = 7.2 Hz, 3H), 0.94 ppm (d, J = 7.0 Hz, 3H); 13C NMR
Scheme 3. Stereochemistry of azaenolate formation and alkylation.
L=large substituent, S=small substituent.
Angew. Chem. Int. Ed. 2008, 47, 5207 –5210
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 5209

Communications
(CDCl3, 100 MHz): d = 184.4, 155.5, 136.6, 116.7, 82.9, 73.4, 47.9, 43.1,
[1]a) D. Enders in Asymmetric Synthesis, 1st ed., Vol. 3 (Ed.: J. D.
Morrison), Academic Press, New York, 1984, pp. 275 – 339; b) A.
Job, C. F. Janeck, W. Bettray, R. Peters, D. Enders, Tetrahedron
2002, 58, 2253 – 2329.
[2]For asymmetric alkylation of cyclic ketones through imines. See:
A. I. Meyers, J. Am. Chem. Soc. 1976, 98, 3032 – 3033; A. I.
Meyers, D. R. Williams, G. W. Erickson, S. White, M. Druelinger,
J. Am. Chem. Soc. 1981, 103, 3081 – 3087; S.-I. Hashimoto, K.
Koga, Tetrahedron Lett. 1978, 19, 573 – 576; S.-I. Hashimoto, K.
Koga, Chem. Pharm. Bull. 1979, 27, 2760 – 2766.
[3]Some progress has been made toward catalytic asymmetric
ketone allylation through allylic carbonate species, but a general
solution remains elusive. See for example: W.-H. Zheng, B.-H.
Zheng, Y. Zhang, X.-L. Hou, J. Am. Chem. Soc. 2007, 129, 7718 –
7719; J. Daniel, J. F. Hartwig, J. Am. Chem. Soc. 2007, 129, 7720 –
7721; B. M. Trost, J. Xu, J. Am. Chem. Soc. 2005, 127, 17180 –
17181; J. F. Hartwig, T. Graening, J. Am. Chem. Soc. 2005, 127,
17192 – 17193.
[4]Other hydrolytic and oxidative methods are available, but have
not been widely used. See: D. Enders, L. Wortmann, R. Peters,
Acc. Chem. Res. 2000, 33, 157 – 169.
[5]J. Qin, G. K. Friestad, Tetrahedron 2003, 59, 6393 – 6402; G. K.
Friestad, J. Qin, J. Am. Chem. Soc. 2000, 122, 8329 – 8330.
[6]For example, alkylation through SAMP hydrazones gives: 31
(61%; b/a = 97:3), 32 (60%; b/a > 99:1), 37 (60%; b/a =
86:14). See Ref. [1a].
37.6, 35.6, 35.1, 26.7, 25.8, 24.8, 21.5, 19.3, 17.3, 10.4 ppm; ESI-MS:
m/z [M + H]+ calcd for C18H29N2O2: 305.44, found 305.1.
General procedure for hydrazone hydrolysis and ACC recovery:
p-TsOH·H2O (9.424 g; 49.54 mmol) was added to a stirred solution of
15 (7.541 g, 24.77 mmol) in acetone (100 mL). The mixture was stirred
for 15 min and then partitioned between Et2O and saturated aqueous
NaHCO3. The aqueous phase was extracted with Et2O (2 ” 250 mL),
and the combined organic extracts were washed with brine, dried over
MgSO4, filtered, and evaporated under reduced pressure to give a
colorless oil that was used directly for GC analysis.[11] Analysis was
conducted under conditions (508C; 15 psi) that gave baseline
separation of the enantiomers of an independently prepared racemic
mixture of 7. Flash chromatography of the remaining crude reaction
mixture over silica gel using Et2O/pentane (5:95) gave 7 (2.933 g,
94%) as a colorless oil. Spectroscopic data was identical to that
reported previously.[10] Continued flash chromatography using
EtOAc/hexanes (25:75) gave 38 (5.737 g, 98%) as a white solid.
1H NMR (CDCl3, 400 MHz): d = 4.25 (dd, J = 8.1, 4.1 Hz, 1H), 3.40–
2.26 (m, 1H), 2.08 (s, 3H), 2.06–1.96 (m, 2H), 1.95 (s, 3H), 1.90–1.70
(m, 2H), 1.34–1.24 (m, 1H), 1.23 (s, 3H), 1.20–1.16 (m, 1H), 1.14 ppm
(s, 3H); 13C NMR (CDCl3, 100 MHz): d = 173.3, 155.1, 83.1, 73.2, 48.1,
42.9, 35.5, 26.8, 25.8, 25.5, 21.4, 20.1, 19.3 ppm; ESI-MS: m/z [M + H]+
calcd for C13H21N2O2: 237.32, found 237.1. 38 (5.729 g; 24.24 mmol)
was then combined with HONH2·HCl (6.731 g; 96.86 mmol) in THF/
H2O (4:1, 250 mL) and stirred for 6 h. The resulting solution was
concentrated and partitioned between EtOAc and saturated aqueous
NaHCO3. The aqueous phase was extracted with EtOAc (2 ”
300 mL), and the combined organic extracts were washed with
brine, dried over MgSO4, filtered, and evaporated to give a light-
yellow solid. Flash chromatography over silica gel using EtOAc/
hexanes (25:75) gave 6 (4.519 g, 95%) as a white solid.
[7]J. dꢀAngelo, Tetrahedron 1976, 32, 2979 – 2990.
[8]For related anion directing effects, see: R. M. Adlington,
A. G. M. Barrett, Acc. Chem. Res. 1983, 16, 55 – 59; W. G.
Kofron, M.-K. Yeh, J. Org. Chem. 1976, 41, 439 – 442.
[9]Prepared from ( +)-camphor sulfonic acid. See: T. H. Yan, V.
Chu, T. C. Lin, C. H. Wu, L. H. Liu, Tetrahedron Lett. 1991, 32,
4959 – 4962.
Received: February 20, 2008
Revised: April 4, 2008
Published online: June 4, 2008
[10]L. E. Hightower, L. R. Glasgow, K. Stone, D. A. Albertson,
H. A. Smith, J. Org. Chem. 1970, 35, 1881 – 1886.
[11]Performed on
a 20 m ” 0.25 mm Chiraldex GTA column
(Advanced Separation Technologies).
Keywords: asymmetric synthesis · carbanions ·
carbonylcompounds · C–C coupilng · diazo compounds
.
5210
www.angewandte.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 5207 –5210