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7
Nucleophilic Addition to Unsaturated Nitrogen
7.1
Nucleophilic Addition to NyN Double Bonds
In contrast with the large number of addition reactions to CbO, and CbN double
bonds, only a few examples of nucleophilic addition to NbN double bonds have
been investigated [1]. In particular, asymmetric syntheses using NbN components
as electrophiles have been rarely developed, despite the remarkable potential of this
type of reaction [2–4]. For example, the metal-catalyzed addition of 2-keto esters
to azodicarboxylates furnished chiral b-amino a-hydroxy esters which are pharma-
ceutically important intermediates [4b]. Several interesting asymmetric organocata-
lytic reactions based on use of azodicarboxylates as NbN electrophiles have been
reported very recently [5–8]. These contributions, which are summarized below,
emphasized the high suitability of chiral organocatalysts for these a-amination re-
actions of ketones and aldehydes. The basic reaction scheme is shown in Scheme
7.1. The resulting products of type 4 or 5 bearing an a-amido carbonyl framework
are of interest for the preparation of a wide variety of important chiral building
blocks, e.g. a-amino acids and b-amino alcohol derivatives.
To start with the a-amination of ketones, the Jørgensen group reported a highly
enantioselective addition of ketones, 1, to azodicarboxylates, 3, as NbN component
[5]. The l amino acid l-proline was found to be a highly efficient catalyst. In a
first screening using a model reaction (Scheme 7.2) it was found that diethyl
Asymmetric Organocatalysis. Albrecht Berkessel and Harald GrogerCopyright 8 2005 WILEY-VCH Verlag GmbH & Co. KGaA, WeinheimISBN: 3-527-30517-3
R1
O
CH2
Direct α-amination
+ Chiral OrganocatalystN
N+
1 (R1=alkyl,benzyl)
2 (R1=H)
non-modifiedketone or aldehyde
as donor
R2
O
R3O
O
OR3N
HN
O
OR3
R1
OR3
O
O
R2
*
3
electrophilic N=Nsubstrate as acceptor
4 (R1=alkyl,benzyl)
5 (R1=H)
Scheme 7.1
245
azodicarboxylate was a more promising NbN substrate than its iso-propyl and tert-butyl analogs (for which enantioselectivity was lower). In addition, the highest
enantioselectivity was obtained when acetonitrile was used as a solvent (Scheme
7.2). Dichloromethane, e.g., led to substantially lower yields and ee. It is worthy of
note that the reactions can also be conducted efficiently in the absence of a solvent.
For such a reaction under neat conditions higher yields and comparable enantio-
selectivity of up to 93% ee were observed, even when the amount of catalyst was
reduced to 5 mol% [5].
Under optimized conditions the organocatalytic a-amination has been performed
successfully with a broad range of ketones, as shown in Scheme 7.3. In the pres-
ence of 10 mol% l-proline as catalyst the a-amination proceeds with formation of
the desired products 4 in high yields (up to 92%) and with good to excellent enan-
tioselectivity in the range 79–99% ee for the isolated products (selected examples
are shown in Scheme 7.3) [5]. Good regioselectivity is also observed. The ratio of
the two types of regioisomeric compound is in the range 76:24 to 91:9. Another ad-
vantage of this l-proline-catalyzed a-amination is the simplicity of the reaction. It
can be conducted at room temperature and is based on the use of an inexpensive
and readily available catalyst. Isolation by extraction after addition of water is also
very practical.
Extension of this proline-catalyzed a-amination to the use of aldehydes as start-
ing materials has been described independently by the Jørgensen and List groups
[6, 7]. The principle of the reaction and some representative examples are shown
in Scheme 7.4. The practicability is high – comparable with that of the analogous
reaction with ketones described above. For example, in the presence of 5 mol%
l-proline as catalyst propanal reacts with azodicarboxylate 3a at room temperature
in dichloromethane with formation of the a-aminated product 5a in 87% yield and
with 91% ee [7]. Good yields and high enantioselectivity can be also obtained by
use of other types of solvent, e.g. toluene and acetonitrile. The products of type 5
were isolated simply by addition of water, extraction with ether, and subsequent
evaporation.
H3C
O
+ L-proline (5-20 mol%)NN
+
1a
CH3
O
EtO
O
OEt NHN
O
OEtH3C
OEt
O
O
CH33a4a
Solvent
AcetonitrileDichloromethane
NeatNeat
Cat. amount[mol%]
2020205
React. timefor full conv. [h]
52766565
ee[%]
96919293
solvent or neat conditions;complete conversion
a) under neat conditions, 2 equiv. of ketone were used.
a)
Scheme 7.2
246 7 Nucleophilic Addition to Unsaturated Nitrogen
The reaction also proceeds efficiently when smaller amounts of catalyst are used.
For example, the analogous synthesis of 5a gave 92% yield and 84% ee in the
presence of only 2 mol% l-proline (compared with 93% yield and 92% ee with
50 mol% catalyst) [7]. This reaction has already been performed on a gram scale.
R1
O
+ L-proline (10 mol%)NN
+
1a
R2
O
EtO
O
OEt NHN
O
OR3
R1
OR3
O
O
R23a
4
acetonitrile,room temperature,
reaction time: 10-96h
Selected examples
NHN
O
OEtH3C
OEt
O
O
CH3
4a80% yield93% ee
regioisomeric ratio 91:9
NHN
O
OEtH3C
OEt
O
O
4b92% yield94% ee
regioisomeric ratio 82:18
Bn
NHN
O
OEtOEt
O
O
CH3
4c79% yield93% ee
H3C NHN
O
OEtOEt
O
O
4d67% yield79% ee
Scheme 7.3
H
O
+ L-proline (2-50 mol%)NN
+
2
R1
O
R2O
O
OR2 NHN
O
OR2
H
OR2
O
O
R13
5
dichloromethaneroom temperature,
reaction time: 45min - 5h
Selected examples
NHN
O
OEtH
OEt
O
O
CH3
5a87% yield91% ee
(cat. amount: 5 mol%)
NHN
O
OEtH
OEt
O
O
5b77% yield90% ee
(cat. amount: 10 mol%)
NHN
O
Oi-PrH
Oi-Pr
O
O
CH3
5c91% yield88% ee
(cat. amount: 10 mol%)
NHN
O
Ot-BuH
Ot-Bu
O
O
CH3
5d99% yield89% ee
(cat. amount: 10 mol%)
CH3
(3a: R2=Et;
3b: R2=i-Pr;
3c: R2=t-Bu)
(1.5 equiv.)
Scheme 7.4
7.1 Nucleophilic Addition to NbN Double Bonds 247
One drawback, however, is that the products 5 are unstable during extended
storage towards racemization. This can be circumvented by converting the alde-
hydes 5 in situ into derivatives. Depending on the reaction conditions amino alco-
hols 6 or oxazolidinones 7 are obtained; these also are valuable intermediates. The
two types of reductive modification are shown in Schemes 7.5 and 7.6, respectively.
Such in situ reductions are performed by treatment with sodium borohydride.
The List group synthesized a broad variety of N-protected amino alcohols 6 by
proline-catalyzed a-amination of aldehydes (Scheme 7.5) [6]. Under optimized con-
ditions, the desired products of type 6 were obtained in high yields (93–99%) and
with excellent enantioselectivity (up to >95% ee). Acetonitrile was found to be the
preferred solvent and a catalytic amount (10 mol%) of proline was used.
The a-amination of aldehydes and subsequent reduction to form oxazolidinones
(Scheme 7.6) was developed by the Jørgensen group [7]. In the presence of
10 mol% l-proline as catalyst a variety of aldehydes reacted with azodicarboxylates,
3a and 3a, affording the oxazolidinones 7 after subsequent reduction with borohy-
dride and cyclization. Selected examples of the synthesis of products 7, which were
obtained in yields up to 92% and with enantioselectivity up to 95% ee, are shown
in Scheme 7.6.
Several transformations of 6 and 7 were also conducted successfully [6, 7]. For
example, oxidation of the aldehyde group of the N-protected amino aldehydes 7
and subsequent standard transformations lead to non-proteinogenic optically active
a-amino acid esters [7].
With regard to the mechanism of the a-amination step, the stereochemistry has
been explained on the basis of a transition state involving a proline–enamine struc-
H
O
NN
+
2
R
O
BnO
O
OBn NHN
O
OBnHO
OBn
O
R3d
6
1. L-proline (10 mol%), acetonitrile, 0 °C - r.t., reaction time: 3h
2. NaBH4, EtOH
Selected examples
NHN
O
OBnHO
OBn
O
CH3
6a97% yield>95% ee
NHN
O
OBnHO
OBn
O
i-Pr
6b99% yield96% ee
NHN
O
OBnHO
OBn
O
t-Bu
6c94% yield97% ee
NHN
O
OBnHO
OBn
O
Bn
6d95% yield>95% ee
(1.5 equiv.) (Bn = benzyl)
Scheme 7.5
248 7 Nucleophilic Addition to Unsaturated Nitrogen
ture. This proposed transition state is analogous to those calculated by Houk et al.
for the intramolecular aldol reaction [9a] and proposed for intermolecular aldol
and Mannich reactions [9b].
In conclusion, the organocatalytic asymmetric a-amination of aldehydes and
ketones using proline as catalyst is a new and attractive access to optically active
N-protected a-amino aldehydes and ketones and related derivatives, e.g. a-amino
acid esters.
7.2
Nucleophilic Addition to NyO Double Bonds
In addition to nucleophilic addition to NbN double bonds, very recently the Mac-
Millan group, the Hayashi group, Zhong, and the Cordova group independently
demonstrated that additions of aldehydes to the NbO double bond also are cata-
lyzed by organocatalysts [10–13]. Nitrosobenzene was used as the NbO compound
and l-proline as the organocatalyst. This asymmetric a-aminooxylation is useful for
synthesis of a-hydroxyaldehydes and a-hydroxyketones, which are versatile inter-
mediates in many organic transformations [14]. It is worthy of note that the car-
bonyl component can be used directly without prior modification, which simplifies
the process. This reaction has also been found to proceed highly enantioselectively.
The concept of the reaction is shown below in Scheme 7.7 [10–13].
It should be added that an analogous, previously developed [15], metal-catalyzed
synthesis, based on use of BINAP–AgOTf as catalyst, is also available. This effi-
H
O
NN
+
2
R1
O
R2O
O
OR2
3a,d 7
1. L-proline (10 mol%), dichloromethane room temperature
2. NaBH4, MeOH3. 0.5N NaOH
Selected examples
7a67% yield93% ee
7b77% yield95% ee
7c92% yield93% ee
7d70% yield91% ee
(1.5 equiv.)
NO
R1
HN
O
O
OR2
(3a: R2=Et;
3d: R2=Bn)
NO
CH3
HN
O
O
OEtNO
C2H5
HN
O
O
OEt NO
HN
O
O
OEtNO
i-Pr
HN
O
O
OBn
Scheme 7.6
7.2 Nucleophilic Addition to NbO Double Bonds 249
cient route, developed by Yamamoto et al., is highly enantioselective in the pres-
ence of tin enolates of ketones as donors [15].
The MacMillan group initially conducted this a-aminooxylation of nitrosoben-
zene in different solvents using propanal as aldehyde in the presence of 10 mol%
l-proline as catalyst [10]. The corresponding optically active aldehydes were formed
with excellent enantioselectivity of 94–98% ee in a wide range of solvents. With re-
gard to yield, however, chloroform was found to be the solvent of choice, although
yields were also good in acetonitrile and benzene. Under optimized reaction condi-
tions (chloroform as solvent and reaction temperature þ4 �C) the amount of cata-
lyst was optimized. In the presence of 10 mol% proline 88% yield and 97% ee were
obtained and the reaction time was very short, 20 min only. High efficiency was
also observed when the amount of catalyst was reduced to 5 and 2 mol%. Enantio-
selectivity remained excellent, 97% ee, and yields were still high, but the reaction
time was slightly prolonged, 45 min for 5 mol% and 2 h for 2 mol%; these condi-
tions are still very attractive. The reaction is also highly enantioselective in the
presence of only 0.5 mol% catalyst, although reaction time is significantly longer
at 18 h (68% yield; 94% ee). An overview of optimization of catalytic loading is
shown in Scheme 7.8.
Investigation of the range of substrates showed this new proline-catalyzed a-
aminooxylation route to be highly general [10]. The products were obtained in
good to high yields and excellent enantioselectivity in the range 97–99% ee were
obtained, irrespective of the pattern of substitution of the aldehydes [10]. An over-
view of the range of substrates under the optimized reaction conditions found
by the MacMillan group is shown in Scheme 7.9. As examples, hexanal and 3-
methylbutanal derived products, (R)-11b and (R)-11c, were obtained with yields of
79 and 85% and enantioselectivity of 98% ee and 99% ee, respectively. Because of
the mild reaction conditions electron-rich p-systems also react efficiently, although
these substrates are prone to oxidative degradation. Thus, aldehydes which contain
olefinic and indolic functional groups were successfully converted into the desired
products (R)-11d and (R)-11f with yields of 80 and 83% and high enantioselectivity
of 99 and 98% ee, respectively. It should be added that the a-oxyaldehyde products
were most conveniently isolated as the corresponding primary alcohols. Other
R1
O
CH2α-aminooxylation
+ Chiral OrganocatalystON+
8 (R1=H)
9 (R1=alkyl)
non-modifiedketone or aldehyde
as donor
R2O
R1
O
R2
*
10
electrophilic N=Osubstrate as acceptor
11 (R1=H)
12 (R1=alkyl)
NH
Scheme 7.7
250 7 Nucleophilic Addition to Unsaturated Nitrogen
H
O L-proline (cat. amount)CHCl3, +4 °C
O
N+
8a
CH3
OH
O
10 11a
CH3
Entry
1
2
3
4
5
Catalytic amount[mol%]
10
5
2
1
0.5
Yield of 4a[%]
88
86
88
83
68
ee[%]
97
97
97
97
94
Reactiontime
20 min
45 min
2 h
8 h
18 h
NH
Scheme 7.8
H
O
R O
N
OH
O
CH3
NH
OH
O
n-BuNH
OH
O
NH
OH
O
NH
OH
O
NH
NH
OH
O
RNH
OH
O
i-PrNH
L-proline (5 mol%)CHCl3, +4 °C, 4 h
+
8 10 11
Selected examples
(R )-11a88% yield97% ee
(2 mol% of proline were used here)
(R )-11b79% yield98% ee
(R )-11c85% yield99% ee
(R )-11d80% yield99% ee
(10 mol% of proline were used here)
(R )-11e60% yield99% ee
(R )-11f83% yield98% ee
Scheme 7.9
7.2 Nucleophilic Addition to NbO Double Bonds 251
transformations, e.g. into a 1,2-amino alcohol, were also described by the MacMil-
lan group [10].
In parallel, Zhong reported the a-aminooxylation of aldehydes, and in-situ deriva-
tization into 1,2-diols, also using l-proline as catalyst [11]. a-Aminooxylation of
isovaleraldehyde with nitrosobenzene at room temperature with 20 mol% catalyst
was studied as model reaction. Because the oxyaldehyde product was found to
be unstable during purification on silica gel, it was converted in situ into the 2-ami-
noxy alcohol (R)-13b. For this two-step, one-pot reaction a high yield (82%) of the
product (R)-13b and excellent enantioselectivity of 99% ee was obtained (Scheme
7.10) [11]. Investigation of the substrate range showed the corresponding products
13 were obtained with excellent enantioselectivity in the range 94–99% ee. Selected
examples are shown in Scheme 7.10.
Zhong rationalized the enantioselectivity by proposing an enamine mechanism
which proceeds via the chair transition state shown in Figure 7.1 [11]. In this tran-
sition state, the Si face of an E enamine formed from the aldehyde and the catalyst
l-proline approaches the less-hindered oxygen atom of nitrosobenzene leading to
the chiral product with (R) configuration. This mechanism is in accordance with
the proposed reaction mechanism for the aldol reaction (see chapter 6.2).
H
O
R ON
O
CH3
NH
OHO
i-PrNH
OH
ONH
Ph
OHO
OH
NH
O
Ph
O
OH
NH
NHBoc
O
RNH
OH
OOH
n-PrNH
1. L-proline (20 mol%) DMSO, RT, 10-20 min
2.NaBH4, EtOH
+
8 10 13
Selected examples
(R )-13a60% yield
97% ee
(R )-13b82% yield
99% ee
(R )-13c71% yield
99% ee
(R )-13d86% yield
99% ee (R )-13e54% yield
99% ee
(R )-13f61% yield
94% ee
n
Scheme 7.10
252 7 Nucleophilic Addition to Unsaturated Nitrogen
The Hayashi group investigated the a-aminoxylation of propanal with nitroso-
benzene in the presence of 30 mol% l-proline as model reaction [12a]. Because of
the instability of the product, it was again converted directly into the corresponding
a-aminoxy alcohol. Investigation of a variety of solvents revealed that acetonitrile
was preferred, giving the desired product (R)-13a in quantitative yield and with ex-
cellent enantioselectivity (98% ee). Yields were lower at a reaction temperature of
0 �C than at�20 �C, because of the occurrence of side-reactions. Investigation of the
range of substrates emphasized the high generality of this new, proline-catalyzed
a-aminooxylation route [12a]. After reaction for 24 h the resulting products were
formed in good to high yields, and excellent enantioselectivity in the range 95–
99% ee was obtained irrespective of the pattern of substitution of the aldehyde
[12a]. Selected examples are shown in Scheme 7.11. Both aliphatic and aromatic
aldehydes were good substrates, affording, for example, products of types (R)-13dand (R)-13g in yields of 70% and 62%, respectively, and with high enantioselectivity
– 99% ee for both reactions.
Fig. 7.1. Transition state proposed for the reaction. (From Ref. [11]).
H
O
R ON
O
CH3
NH
OHO
i-PrNH
OH
ONH
Ph
OHO
OH
PhNH
O
RNH
OH
OOH
n-PrNH
1. L-proline (30 mol%) CH3CH, -20 °C, 24 h
2.NaBH4
+
8 10 13
Selected examples
(R )-13aquantitative yield
98% ee
(R )-13b77% yield
97% ee
(R )-13c81% yield
95% ee
(R )-13d70% yield
99% ee
(R )-13g62% yield
99% eeScheme 7.11
7.2 Nucleophilic Addition to NbO Double Bonds 253
The effect of the amount of catalyst (which is high, approximately 30 mol%) on
this model reaction was also studied. Conducting the reaction with 10 mol%
l-proline resulted in the same yield and enantioselectivity (quantitative yield for
(R)-13a, and 98% ee; reaction time 24 h). A further decrease to 5 mol% led, how-
ever, to a slightly lower yield of 81%, although enantioselectivity was not affected
(98% ee) [12a].
This a-aminooxylation has subsequently been successfully extended to the use of
ketones as donors [12]. For example, use of cyclohexanone as donor led to (R)-12ain 79% yield and with an excellent enantioselectivity of >99% ee (Scheme 7.12)
[12a]. Very recently, the Cordova group reported further examples of this proline-
catalyzed a-aminooxylation [13]. In addition, this method has been successfully ap-
plied in the synthesis of corresponding chiral 1,2-diols after subsequent derivatiza-
tion [13]. Furthermore, computational studies of transition states were carried out
[13b].
In summary, the organocatalytic asymmetric a-aminooxylation of aldehydes and
ketones with proline as catalyst is a highly enantioselective means of preparation of
a-hydroxy carbonyl compounds, and their derivatives. Because this field has been
developed only recently, more examples and work on extension of organocatalyst
screening and process development can be expected in the near future.
References
1 For general reviews of a-amination
of carbonyl compounds, see: (a) C.
Greck, J. P. Genet, Synlett 1997,741–748; (b) J. P. Genet, C. Greck,
D. Lavergne in: Modern AminationMethods (Ed.: A. Ricci), Wiley–VCH,
Weinheim, 2000, Chapter 3.
2 For selected examples of diastereo-
selective asymmetric syntheses using
chiral enolates and NbN components
as electrophiles, see: (a) C. Gennari,
L. Colombo, G. Bertolini, J. Am.Chem. Soc. 1986, 108, 6394–6395;(b) D. A. Evans, T. C. Britton, R. L.
Dorow, J. F. Dellaria, Jr., J. Am.
Chem. Soc. 1986, 108, 6395–6397; (c)L. A. Trimble, J. C. Vederas, J. Am.Chem. Soc. 1986, 108, 6397–6399;(d) W. Oppolzer, R. Moretti, Helv.Chim. Acta 1986, 69, 1923–1926.
3 For ‘‘indirect’’ enantioselective
catalytic syntheses using preformed
enolsilanes and NbN components,
see: (a) D. A. Evans, D. S. Johnson,
Org. Lett. 1999, 1, 595–598; (b) Y.Yamashita,H. Ishitani, S. Kobayashi,
J. Can. Chem. 2000, 78, 666–672.4 For ‘‘direct’’ enantioselective catalytic
syntheses using unmodified enolates,
and NbN components, see: (a) D. A.
O
O
N ONH
Ocat. L-proline, 0 °C
+
9a 10 (R )-12a79% yield>99% ee
Scheme 7.12
254 7 Nucleophilic Addition to Unsaturated Nitrogen
Evans, S. G. Nelson, J. Am. Chem.Soc. 1997, 119, 6452–6453; (b) K. Juhl,K. A. Jørgensen, J. Am. Chem. Soc.2002, 124, 2420–2421.
5 N. Kumaragurubaran, K. Juhl,
W. Zhuang, A. Bøgevig, K. A.
Jørgensen, J. Am. Chem. Soc. 2002,124, 6254–6266.
6 B. List, J. Am. Chem. Soc. 2002, 124,5656–5657.
7 A. Bøgevig, K. Juhl, N.
Kumaragurubaran, W. Zhuang,
K. A. Jørgensen, Angew. Chem. 2002,144, 1868–1871; Angew. Chem. Int. Ed.2002, 41, 1790–1793.
8 R. O. Duthaler, Angew. Chem. 2003,115, 1005–1008; Angew. Chem. Int. Ed.2003, 42, 975–978.
9 (a) S. Bahmanyar, K. N. Houk,
J. Am. Chem. Soc. 2001, 123, 12911–12912; (b) B. List, Synlett 2001, 1675–1686.
10 S. P. Brown, M. P. Brochu, C. J.
Sinz, D. W. C. MacMillan, J. Am.Chem. Soc. 2003, 125, 10808–10809.
11 G. Zhong, Angew. Chem. 2003, 115,4379–4382; Angew. Chem. Int. Ed.Engl. 2003, 42, 4247–4250.
12 (a) Y. Hayashi, J. Yamaguchi, K.
Hibino, M. Shoji, Tetrahedron Lett.2003, 44, 8293–8296; (b) Y. Hayashi,
J. Yamaguchi, T. Sumiya, K. Hibino,
M. Shoji, J. Org. Chem. 2004, 69,5966–5973; (c) Y. Hayashi, J.
Yamaguchi, T. Sumiya, M. Shoji,
Angew. Chem. 2004, 116, 1132–1135;Angew. Chem. Int. Ed. 2004, 43, 1112–1115.
13 (a) A. Bøgevig, H. Sunden, A.
Cordova, Angew. Chem. 2004, 116,1129–1132; Angew. Chem. Int. Ed.2004, 43, 1109–1112; (b) A. Cordova,H. Sunden, A. Bøgevig, M.
Johansson, F. Himo, Chem. Eur. J.2004, 10, 3673–3684.
14 For general reviews of synthesis
of a-oxycarbonyl compounds viahydroxylation, see, for example, F. A.
Davis, B. C. Chen in: Houben–Weyl:Methods of Organic Chemistry (Eds.:G. Helmchen, R. W. Mulzer, E.
Schaumann), Georg Thieme Verlag,
Stuttgart, 1995, Vol. E21, pp. 4497 ff.
15 N. Momiyama, H. Yamamoto, J.Am. Chem. Soc. 2003, 125, 6038–6039.
References 255
