Promotion of asymmetric aza-claisen rearrangement of N-allylic carboxamides using excess base

Article abstract of DOI:10.1055/s-0031-1289899

The aza-Claisen rearrangement of the enolate of N-(Z)-crotyl-N-(S)- phenethylpropanamide did not proceed in the presence of 1.5 equivalents of LHMDS as a base. However, the use of a large excess of base (10 equiv) promoted the reaction to give N-(S)-phenethyl-anti-2,3-dimethylpent-4-enamide with good stereoselectivities (anti/syn = ca. 95:5). An excess of base stabilized the amide enolates and prevented the decomposition to the ketene to prompt the rearrangement of various carboxamides with good stereoselectivity. This reaction provided a new method for the construction of asymmetric quaternary carbon centers. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289899

LETTER
2967
Promotion of Asymmetric Aza-Claisen Rearrangement of N-Allylic
Carboxamides Using Excess Base
A
symmetric
A
za-Clais
a
e
n
Rearran
k
gement of
N
-
o
A
llylic Carb
t
oxamid
o
es Yoshizuka, Takeshi Nishii, Hiromi Sasaki, Junko Kitakado, Noriko Ishigaki, Shinobu Okugawa,
Hiroto Kaku, Mitsuyo Horikawa, Makoto Inai, Tetsuto Tsunoda*
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima 770-8514, Japan
Fax +81(88)6553051; E-mail: tsunoda@ph.bunri-u.ac.jp
Received 12 July 2011
O
1) LHMDS (toluene or n-hexane solution)
toluene, –78 °C
Abstract: The aza-Claisen rearrangement of the enolate of N-(Z)-
crotyl-N-(S)-phenethylpropanamide did not proceed in the presence
of 1.5 equivalents of LHMDS as a base. However, the use of a large
excess of base (10 equiv) promoted the reaction to give N-(S)-phen-
ethyl-anti-2,3-dimethylpent-4-enamide with good stereoselectivi-
ties (anti/syn = ca. 95:5). An excess of base stabilized the amide
enolates and prevented the decomposition to the ketene to prompt
the rearrangement of various carboxamides with good stereoselec-
tivity. This reaction provided a new method for the construction of
asymmetric quaternary carbon centers.
X
N
Ph
2) 120 °C, 6 h
O
O
1a: X = Me
1b: X = OH
1c: X = NH2
S
R
X
X
R
S
+
N
Ph
N
Ph
H
H
(S,R)-3a–c
(R,S)-2a–c
syn
+
Key words: aza-Claisen rearrangement, amide enolate, asymmet-
eq 1
ric reaction
O
O
X
S
S
X
R
R
+
N
Ph
N
Ph
H
H
The aza-Claisen rearrangement is a powerful tool in syn-
thetic organic chemistry and has attracted much atten-
tion.1 Previously, we reported that the asymmetric aza-
Claisen rearrangement of the enolates of carboxamides 1
provided 2,3-syn stereochemistry with excellent stereose-
lectivities (syn/anti 99:1, 2/3 = ca. 89:11, Scheme 1).
(S,S)-4a–c
(R,R)-5a–c
anti
O
O
O
HO
N
Ph
N
Ph
n-Bu
This rearrangement was adaptable to carboxamides with
various substituents (X = Me, OH, or NH2 in Scheme 1),
and the major rearrangement products, 2,3-disubstituted
pent-4-enamides 2,2 could be used efficiently as synthetic
precursors for (–)-verrucarinolactone2b and D-allo-isoleu-
cine.2b This methodology was applied to the reactions of
N
Ph
TIPSO
6
7
8
Scheme 1 Aza-Claisen rearrangement of carboxamides
carboxamides 6–8 to synthesize (–)-antimycin A3b,2d,e (–)- Table 1 Optimization of the Reaction Conditions for the Aza-
isoiridomyrmecin,2f (+)-a-skytanthine,2g and (+)-brefeldin
Claisen Rearrangement of 9a
C.2h
O
1) LHMDS (equiv)
solvent, –78 °C
Thus, the aza-Claisen rearrangement has potential for
N
Ph
+
syn
4a
+
5a
broad use in the stereocontrolled construction of naturally
occurring carbon skeletons with 2,3-syn stereochemistry.
However, using the same conditions for the transforma-
tion of 1a, N-(Z)-crotyl propanamide 9a did not undergo
this rearrangement to afford the expected product with
2,3-anti stereochemistry. To overcome this problem, we
examined the reaction under various conditions (solvent,
temperature, additives, and amount of base), and found
that the use of excess base promoted the rearrangement
quite satisfactorily. Herein, we describe the results.
2) 120 °C, time
anti
9a
Entry LHMDS Solvent
(equiv)
Time Yield anti/syna (4a/5a)b
(h)
(%)
c
1
1.5
toluene–n-
6
–
–
hexane or toluene
2
3
4
5
3.0
5.0
5.0
10
toluene
toluene
toluene
toluene
6
6
38
42
58
63
74:26 (10:90)
94:6 (11:89)
93:7 (11:89)
95:5 (11:89)
15
15
a The ratio of (4a + 5a)/(2a + 3a).
SYNLETT 2011, No. 20, pp 2967–2970
Advanced online publication: 23.11.2011
DOI: 10.1055/s-0031-1289899; Art ID: U05211ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
1
1
b The ratio of anti isomers (4a/5a) is shown.
c Complex mixture.

2968
M. Yoshizuk et al.
LETTER
The rearrangement of the enolate of 1a took place in the On the basis of this finding, we then examined the rear-
presence of 1.5 equivalents of LHMDS in toluene at rangement of carboxamides 9b–f,5 because the reaction
120 °C in 85% yield with excellent stereoselectivities with 1.5 equivalents of LHMDS also gave messy products
(Scheme 1). In contrast, the reaction of 9a afforded messy with a small amount of the desired rearrangement prod-
products with no desired rearrangement products and the ucts and none of the starting materials 9b–f. Actually, al-
starting material 9a under the same conditions (Table 1, though the reaction of 9b with 1.5 equivalents of LHMDS
entry 1). However, the use of excess LHMDS led to some gave a poor yield again (Table 2, entry 1), increasing the
improvement in the yields and/or stereoselectivities. amount of base (5 equiv) and prolonging the reaction pe-
When three equivalents of LHMDS were used, 38% of re- riods (48 h) improved the yield (89%) and the stereoselec-
arranged products 2a–5a were obtained with moderate tivity (3S/3R = 88:12,8 Table 2, entry 2). In the cases of
stereoselectivities (anti/syn = ca. 74:26, 5a/4a = 90:10,3 9c–f, excess base also provided good results with high
Table 1, entry 2). The yield of the rearranged products in- yields and high stereoselectivities10 (Table 2, entries 3, 5,
creased to 63% by using a greater excess of base and by 7, 9 vs. entries 4, 6, 8, 10). The level of the stereoselectiv-
extending the reaction periods (Table 1, entries 3–5). Fur- ity (about 90:10) was quite similar to those of the reac-
thermore, the anti vs. syn selectivity was also increased, tions of 1 and 9a. Furthermore, the S-phenethyl group
reaching a ratio of 95:5 in the presence of ten equivalents controlled the absolute configurations at the C-2 and C-3
of LHMDS.4 This good internal asymmetric induction positions. The reaction of 9f indicated that this rearrange-
(anti selectivity) was dependent on the olefin geometry of ment reaction could be applied to the construction of
9a, and the high relative asymmetric induction (5a vs. 4a) asymmetric quaternary carbon centers with good selectiv-
was due to a chiral auxiliary, the S-phenethyl group, on ity.
the nitrogen atom. Thus, this reaction was very useful to
construct 2,3-anti stereochemistry.
Table 2 Scope and Limitation of the Aza-Claisen Rearrangement of 9b–f
Entry
Substrate
LHMDS Temp
(equiv) (°C)
Period Major product
(h)
Minor product
Yield
(%)
Selectivity
(10/11)
O
O
O
1
2
1.5
5.0
120
120
48
48
18
89
75:12
88:12
N
Ph
N
Ph
N
Ph
H
H
R
S
10b
O
9b
9c
11b
O
O
O
O
S
R
3
4
1.5
5.0
120
120
24
24
<30a
94
91:9
91:9
N
N
Ph
Ph
N
Ph
Ph
N
N
Ph
Ph
H
H
H
H
10c
11c
O
R
S
b
c
N
5
6
1.5
5.0
120
24
24
–
–
100d
84
87:13
9d
9e
10d
11d
O
O
O
O
R
b
c
S
7
8
N
Ph
1.5
5.0
120
120
12
12
–
–
N
N
Ph
Ph
N
Ph
H
H
H
77
89:11
10e
11e
O
O
S
R
b
c
N
Ph
9
10
1.5
5.0
120
120
12
12
–
–
N
Ph
88:12e
H
98
R
S
Et
Et
Et
10f
11f
9f
a Difficult to purify.
b Complex mixture.
c Not determined.
d The reaction at 120 °C gave a lower yield (57%).
e 2R,3R and 2S,3S isomers were not detected.
Synlett 2011, No. 20, 2967–2970 © Thieme Stuttgart · New York

LETTER
Asymmetric Aza-Claisen Rearrangement of N-Allylic Carboxamides
2969
E. D.; Smith, A. D.; Thomson, J. E. Org. Biomol. Chem.
2009, 7, 2604. (c) Castro, A. M. M. Chem. Rev. 2004, 104,
2939. (d) Nubbemeyer, U. Synthesis 2003, 961.
When the reaction gave poor results, we suspected that the
decomposition of the enolates of the carboxamides via the
ketene12 was one of the undesired reactions.13 However,
as the reaction of 9 with 1.5 equivalents of LHMDS gave
a complex mixture of products, no direct evidence for this
decomposition pathway could be found. So, N,N-dibenzyl
propanamide (12) was employed as a model compound
for studies of the decomposition pathways of the amide
enolate. First, N,N-dibenzyl propanamide (12) was treated
with 1.5 equivalents of LHMDS at 80 °C for one hour,
giving 83% of recovered 12. However, when the reaction
was conducted at 120 °C for one hour with 1.5 equivalents
of LHMDS, only 46% of 12 was recovered along with
some dibenzylamine. In contrast, use of five equivalents
of LHMDS (120 °C, 1 h) increased the recovery yield of
12 to 86%. These findings suggested the following: 1) de-
compositions occurred at around 120 °C, the temperature
at which the aza-Claisen rearrangement took place, and 2)
excess base stabilized the amide enolates and prevented
the decomposition to ketene and other undesirable side re-
actions (Scheme 2), although the reason was unclear.
(2) (a) Tsunoda, T.; Sakai, M.; Sasaki, O.; Sako, Y.; Hondo, Y.;
Itô, S. Tetrahedron Lett. 1992, 33, 1651. (b) Tsunoda, T.;
Tatsuki, S.; Shiraishi, Y.; Akasaka, M.; Itô, S. Tetrahedron
Lett. 1993, 34, 3297. (c) Itô, S.; Tsunoda, T. Pure Appl.
Chem. 1994, 66, 2071. (d) Tsunoda, T.; Nishii, T.;
Yoshizuka, M.; Yamasaki, C.; Suzuki, T.; Itô, S.
Tetrahedron Lett. 2000, 41, 7667. (e) Nishii, T.; Suzuki, S.;
Yoshida, K.; Arakaki, K.; Tsunoda, T. Tetrahedron Lett.
2003, 44, 7829. (f) Tsunoda, T.; Tatsuki, S.; Kataoka, K.;
Itô, S. Chem. Lett. 1994, 543. (g) Tsunoda, T.; Ozaki, F.;
Shirakata, N.; Tamaoka, Y.; Yamamoto, H.; Itô, S.
Tetrahedron Lett. 1996, 37, 2463. (h) Inai, M.; Nishii, T.;
Mukoujima, S.; Esumi, T.; Kaku, H.; Tominaga, K.; Abe,
H.; Horikawa, M.; Tsunoda, T. Synlett 2011, 1459.
(3) The stereochemistry of the products was determined by the
comparison with the samples, which had been obtained by
the rearrangement of 1a; see ref. 2a.
(4) It was suspected that the basicity of LHMDS was not
sufficient to deprotonate the amides, and stronger bases must
be required. However, the reaction with LDA gave lower
yields and stereoselectivities; see ref. 2a. Furthermore, the
reaction of 9a utilizing s-BuLi (1.5 equiv) gave the same
results as with LHMDS (1.5 equiv).
O
O
(5) Typical Procedure for the Aza-Claisen Rearrangement
To a solution of LHMDS (1.0 M in toluene, 5.0 mL) in
toluene (3 mL) was added a toluene solution (3 mL) of
carboxamide 9d (231 mg, 1.0 mmol) at –78 °C under an
argon atmosphere in a pressure tube.6 After 30 min with
stirring, the reaction mixture was allowed to warm to r.t. and
was sealed. After heating of the sealed solution at 120 °C for
24 h, a sat. aq NaHCO3 (24 mL) was added, and the mixture
was extracted with CH2Cl2 (30 mL), dried (Na2SO4), and
evaporated.7 The residual mixture was purified by SiO2
column chromatography (n-hexane–EtOAc = 3:1) to give
156 mg (68%) of 11d and 39 mg (17%) of a mixture of 10d
and 11d as colorless needles, respectively.
Bn
Δ
O
Bn
Bn
–
N
+
N
N
–
Bn
Bn
Bn
12
Scheme 2 Decomposition of the lithium enolate of 12
Based on Ireland’s investigation14 of Claisen rearrange-
ment of silyl enol ethers derived from esters, we propose
an explanation for the results described in this paper.
Ireland reported that the alkyl substituent on the 1,5-diene
system affected the reaction rate, with the reaction rate of
the less substituted 1,5-diene being considerably slower.
In our investigation, the reaction of 9b,c required a longer
reaction period than that of 1a did. In the case of 9a and
9d–f, it seems feasible that the rate of the reaction was
slowed by steric repulsion caused by the pseudo-axial
substituents on the allylic olefin in the six-membered
chairlike transition state. In this situation, we presumed
that the decomposition of the lithium enolates of 9a–f to
the respective ketenes and other byproducts became the
predominant reaction. However, as mentioned above, the
addition of excess base prevented the decomposition and
promoted the desired rearrangement.
Compound 10d: mp 84.5–85.5 °C (n-hexane–EtOAc).
[a]D21 –94.7 (c 0.65, CHCl3). 1H NMR (400 MHz, CDCl3):
d = 7.40–7.20 (m, 5 H), 5.65 (br d, J = 7.2 Hz, 1 H), 5.13
(quin, J = 7.6 Hz, 1 H), 4.76 (m, 1 H), 4.73 (m, 1 H), 2.45–
2.30 (m, 2 H), 2.09 (ddd, J = 12.5, 5.2, 0.8 Hz, 1 H), 1.72
(dd, J = 1.2, 0.8 Hz, 3 H), 1.47 (d, J = 6.8 Hz, 3 H), 1.11 (d,
J = 6.8 Hz, 3 H). 13C NMR (100 MHz, CDCl3): d = 174.9,
143.24, 143.21, 128.6, 127.3, 126.2, 112.4, 48.5, 42.2, 39.6,
22.4, 21.6, 17.6. IR (ATR): 3269, 2970, 1637, 1542, 1450
cm–1. MS (CI): m/z = 232 [M + H]+ (base peak), 231 [M]+,
128, 105. HRMS (CI): m/z [M + H]+ calcd for C15H22ON:
232.1701; found: 232.1701.
Compound 11d: mp 54.2–55.5 °C (n-hexane–EtOAc);
[a]D21 –84.6 (c 0.43, CHCl3). 1H NMR (400 MHz, CDCl3):
d = 7.40–7.20 (m, 5 H), 5.66 (br d, J = 6.8 Hz, 1 H), 5.13
(quin, J = 7.2 Hz, 1 H), 4.74 (br s, 1 H), 4.68 (br s, 1 H),
2.45–2.30 (m, 2 H), 2.07 (dd, J = 17.2, 10.8 Hz, 1 H), 1.67
(s, 3 H), 1.48 (d, J = 6.8 Hz, 3 H), 1.14 (d, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 175.0, 143.2, 143.1,
128.6, 127.3, 126.2, 112.4, 48.4, 42.1, 39.6, 22.3, 21.5, 17.6.
IR (ATR): 3285, 2970, 1639, 1538, 1450 cm–1. MS (CI):
m/z = 232 [M + H]+ (base peak), 231 [M]+, 128, 105. HRMS
(CI): m/z [M + H]+ calcd for C15H22ON: 232.1701; found:
232.1701.
Acknowledgment
This work was supported partially by a Grant-in-Aid for Scientific
Research (C) from MEXT (the Ministry of Education, Culture,
Sports, Science, and Technology of Japan). We are also thankful to
MEXT-Senryaku, 2008-2012.
References and Notes
(6) An air-tight cylinder for high-pressure experiments is
available at Alltech Associates, Inc.
(7) At this point, the diastereomeric ratio was determined by
GLC or LC.
(1) Percent review of aza-Claisen rearrangement:
(a) Majumdar, K. C.; Bhattacharyya, T.; Chattopadhyay, B.;
Sinha, B. Synthesis 2009, 2117. (b) Davies, S. G.; Garner,
A. C.; Nicholson, R. L.; Osborne, J.; Roberts, P. M.; Savory,
Synlett 2011, No. 20, 2967–2970 © Thieme Stuttgart · New York

2970
M. Yoshizuk et al.
LETTER
(8) Determination of the Stereochemistry of the Products
A 88:12 mixture of 10b and 11b was subjected to
e-mail: deposit@ccdc.cam.ac.uk].
C: The stereochemistries of the major products 10e and 10f
were estimated empirically.
hydroboration(disiamylborane), oxidation (aq NaOH–
H2O2), and heating with PTSA to give 3-methylvalero-
lactone whose specific rotation {[a]D23 –19.8 (c 4.5, CHCl3)}
was compared with its 3R-isomer {[a]D25 +27.6 (c 5.6,
CHCl3)}.9 Thus, the major product 10b was determined to
have the S configuration at the C-3 position.
(9) Konoike, T.; Araki, Y. J. Org. Chem. 1994, 59, 7849.
(10) Determination of the Stereochemistry of the Products
A: A 91:9 mixture of 10c and 11c was subjected to
hydroboration(disiamylborane), oxidation (aq NaOH–
H2O2), and heating with PTSA to give 2-methylvalero-
lactone whose specific rotation {[a]D22 –56.3 (c 2.48,
MeOH)} was compared with its 2S-isomer {[a]D25 +67.3 (c
6.59, CHCl3)}.11 Thus, the major product 10c was
Figure 1 The crystallographic analysis of 10d
(11) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc.
1982, 104, 1737.
determined to have the R configuration at the C-2 position.
B: The stereochemistry of the major product 10d was
confirmed by X-ray analysis as shown in Figure 1.
Crystallographic data (excluding structure factors) for this
structure have been deposited with the Cambridge Crystallo-
graphic Data Centre as supplementary publication numbers
CCDC 832610. Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road,
(12) It was reported that enolates of esters decomposed
completely to ketene at 0 °C; see ref. 11.
(13) Although it was suspected that there were several
decomposition pathways, we could not isolate any
meaningful compounds, not even Claisen-type condensation
products, from the reaction mixtures.
(14) Ireland, R. E.; Mueller, R. H.; Willard, A. K. J. Am. Chem.
Soc. 1976, 98, 2868.
Cambridge, CB2 1EZ, UK [fax: +44(1223)336033 or
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