Highly enantioselective synthesis of N,N-dialkvlbenzamides with aryl-carbonyl axial chirality by rhodium-catalyzed [2+2+2] cycloaddition

Article abstract of DOI:10.1002/chem.200800953

A study was conducted to demonstrate the enantioselective synthesis of axially chiral compounds by cationic rhodium(I)/modified-binapcatalyzed (2+2+2) cycloadditions. The study investigated a rhodium-catalyzed (2+2+2) cycloaddition of malonate-derived 1,6-diyne with N,N-diisopropylalkynylamide, bearing a sterically demanding 2-methoxypropyl group at an alkyne terminus, by employing various axially chiral biarylbisphosphine ligands. The scope of cycloaddition was also examined in terms of N,N-diisopropylalkynylamide. The generality of cycloaddition was examined in terms of 1,6-diyne. It was found that the methyl group at the ortho position of N,N-diisopropylalkynylamide is essential, to construct the stable axial chirality.

Full text of DOI:10.1002/chem.200800953

COMMUNICATION
DOI: 10.1002/chem.200800953
Highly Enantioselective Synthesis of N,N-Dialkylbenzamides with Aryl–
Carbonyl Axial Chirality by Rhodium-Catalyzed [2+2+2] Cycloaddition
Takeshi Suda,[a] Keiichi Noguchi,[b] Masao Hirano,[a] and Ken Tanaka*[a]
2,6-Disubstituted N,N-dialkylbenzamides are known to
exist as atropisomers due to the high rotational barrier
around the aryl–carbonyl single bond.[1] Their interesting
atropisomerism[1] and considerable utility as chiral re-
agents[2] have prompted organic chemists to explore their
asymmetric synthesis.[3–7] Kinetic resolution by Sharpless di-
hydroxylation,[3] and dynamic kinetic resolution of racemic
2-formylnaphthamides by the reaction with a chiral diamine
or an amino alcohol[4] and the proline-catalyzed aldol reac-
tion[5] have been employed as resolution methods. The ste-
Scheme 1. Enantioselective synthesis of N,N-dialkylbenzamides with
aryl–carbonyl axial chirality.
reoselective alkylation of an enantiopure planar chiral (2-
methyl-N,N-diethylbenzamide)chromium complex was re-
ported as a diastereoselective method,[6] and the enantio-
A
with outstanding enantiomeric excesses (>99% ee) by aro-
matization through a cationic rhodium(I)/segphos- or binap-
catalyzed [2+2+2]cycloaddition of 1,6-diynes with N,N-
ACHTREUNG
ACHTREUNG
dialkylalkynylACHTERaUNG mides (Scheme 1).
A
We first investigated a rhodium-catalyzed [2+2+2]cyclo-
addition of malonate-derived 1,6-diyne 1a with N,N-diiso-
propylalkynylamide 2a bearing a sterically demanding 2-me-
thoxypropyl group at an alkyne terminus by employing vari-
ous axially chiral biarylbisphosphine ligands (Table 1). We
were pleased to find that the reactions proceeded to give
the desired axially chiral benzamide (À)-3aa with excellent
ee, and high yield of 3aa was achieved by using binap or
segphos as a ligand (Table 1, entries 1 and 4). When a solu-
tion of 1a in CH2Cl2 was added to a solution of 2a and Rh
catalyst in CH2Cl2, the yields of 3aa were improved further
(Table 1, entries 5 and 6).
lytic enantioselective method has not been realized to date.
Furthermore, N,N-dialkylbenzamides bearing a sterically de-
manding ortho substituent, which possess highly stable axial
chirality, are difficult to prepare by existing methods. Re-
cently, we reported the enantioselective synthesis of axially
chiral compounds by cationic rhodium(I)/modified-binap-
catalyzed [2+2+2]cycloadditions.
first catalytic enantioselective construction of the aryl–car-
bonyl axial chirality of N,N-dialkylbenzamides in high yields
[8,9]
Herein, we report the
[a]T. Suda, Dr. M. Hirano, Prof. Dr. K. Tanaka
Department of Applied Chemistry
Graduate School of Engineering
Tokyo University of Agriculture and Technology
Koganei, Tokyo184-8588 (Japan)
Fax : (+81)42-388-7037
Thus, the scope of this cycloaddition was examined with
respect to N,N-dialkylalkynylamides (Table 2, entries 1–7).
Not only sterically demanding diisopropylamide (2a,
Table 2, entry 1) but also diethylamide (2b, Table 2,
entry 2), dimethylamide (2c, Table 2, entry 3), and 1-piperi-
dinylamide (2d, Table 2, entry 4) furnished the correspond-
ing benzamides with stable axial chirality in high yields with
excellent ee values. Furthermore, the reactions of not only
2-methoxypropyl (2a) but also tertiary (2e, Table 2,
entry 5),[10] secondary (2 f, Table 2, entry 6), and primary
(2g, Table 2, entry 7) alkyl-substituted alkynylamides gave
E-mail: tanaka-k@cc.tuat.ac.jp
[b]Prof. Dr. K. Noguchi
Instrumentation Analysis Center
Tokyo University of Agriculture and Technology
Koganei, Tokyo184-8588 (Japan)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200800953.
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6593

Table 1. Screening of ligands for Rh-catalyzed enantioselective synthesis
Table 2. RhI+/segphos- or binap-catalyzed enantioselective synthesis of
of axially chiral N,N-dialkylbenzamide 3aa.[a]
axially chiral N,N-dialkylbenzamides 3.[a]
Entry
Diyne 1
Monoyne 2
Product 3/ Yield[%][b],ee[%]
1
2
3
1a (E=CO2Bn)
1a (E=CO2Bn)
1a (E=CO2Bn)
2a (R=iPr)
2b (R=Et)
2c (R=Me)
(À)-3aa 92,>99
(À)-3ab 94,>99
(+)-3ac 90,>99
[b]
Entry
Ligand
Time [h]Yield [%]
ee [%]
1
2
3
4
(S)-binap
1
5
1
1
1
3
80
70
59
82
84
90
>99
>99
98
>99
>99
>99
(S)-tol-binap
(S)-H8-binap
(S)-segphos
(S)-binap
4
1a (E=CO2Bn)
2d
2e
(À)-3ad 98,>99
(À)-3ae 90,>99
5[c]
6[c]
(S)-segphos
[a][Rh ACHTREUNG(cod)2]BF4 (0.0050 mmol), ligand (0.0050 mmol), 1a (0.10 mmol),
2a (0.11 mmol, 1.1 equiv), and CH2Cl2 (1.5 mL) were used. A solution of
1a and 2a was added to a solution of Rh catalyst. [b]Yield of isolated
product. [c]A solution of 1a was added to a solution of 2a and Rh cata-
lyst.
5[c]
1a (E=CO2Bn)
the corresponding benzamides with stable axial chirality in
high yields with excellent ee values. In the case of the alky-
nylamides 2a-e bearing tertiary substituents at an alkyne
terminus, segphos is a suitable ligand (Table 2, entries 1–5).
On the other hand, binap is a suitable ligand for the alkynyl-
6[d]
1a (E=CO2Bn)
2 f
(+)-3af >99,>99
ACHTREUNGamides 2 f and 2g bearing a secondary or primary substitu-
ent at an alkyne terminus (Table 2, entries 6 and 7).
The generality of this cycloaddition was subsequently ex-
amined with respect to 1,6-diynes. Thus, tosylamide- (1b,
Table 2, entry 8) and ether-linked (1c, Table 2, entry 9)[10]
1,6-diynes could participate in this reaction to give the cor-
responding axially chiral benzamides in high yields with ex-
cellent ee values. The methyl group at the ortho position of
N,N-dialkylbenzamides is necessary to construct the stable
axial chirality. Although the reaction of terminal 1,6-diyne
1d with 2a furnished the corresponding benzamide 3da in
good yield, 3da does not possess stable axial chirality at
room temperature despite of the sterically demanding sub-
stituents on the nitrogen atom and at the ortho position
(Scheme 2).[11]
7[d]
1a (E=CO2Bn)
2g
(+)-3ag 96,>99
8[e]
9[c]
1b (Z=NTs)
1c (Z=O)
2a
2a
(À)-3ba 85,>99
(À)-3ca 81,>99
[a]Reactions were conducted by using [Rh ACTHRE(UGN cod)2]BF4 (0.0075 mmol),
(S)-segphos (0.0075 mmol), 1 (0.15 mmol), 2 (0.165 mmol, 1.1 equiv), and
CH2Cl2 (2.0 mL) at room temperature for 1 h. [b]Yield of isolated prod-
uct. [c] 2: 2 equiv. [d]Ligand: ( S)-binap. [e]CH Cl2: 1.5 mL.
2
Next, the reaction of a N,N-dialkylalkynylamide bearing a
2-substituted phenyl group at an alkyne terminus with a 1,6-
diyne was examined, which would construct both aryl–car-
bonyl and aryl–aryl axial chiralities in
a single step
(Scheme 3).[12] We were pleased to find that alkynylamide
2h bearing a o-tolyl group at an alkyne terminus reacted
with 1,6-diyne 1c in the presence of the RhI+/(S)-binap cata-
lyst to give the corresponding axially chiral biarylbenzamide
(À)-3ch in high yield with excellent enantio- and diastereo-
selectivity.[10] Similarly, the reaction of 2-bromo-substituted
alkynylamide 2i also provided the corresponding axially
Scheme 2. RhI+/segphos-catalyzed reaction of terminal 1,6-diyne 1d with
monoyne 2a.
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N,N-Dialkylbenzamides with Aryl–Carbonyl Axial Chirality
COMMUNICATION
ortho-(isopropyl)benzamide (3af, Table 3, entry 6) was grad-
ually racemized and ortho-ACHTER(UNG n-butyl)benzamide (3ag,
Table 3, entry 7) was completely racemized after 24 h. Thus,
the substituents on the nitrogen center and at the ortho posi-
tion of N,N-dialkylbenzamides significantly affect the ther-
mal stability of axially chirality.
In conclusion, we have developed the first catalytic enan-
tioselective synthesis of axially chiral N,N-dialkylbenzamides
in high yields with outstanding ee values (>99% ee) by a
cationic rhodium(I)/segphos- or binap-catalyzed [2+2+2]cy-
cloaddition of 1,6-diynes with N,N-dialkylalkynylamides.
Furthermore, the use of N,N-dialkylalkynylamides bearing a
2-substituted phenyl group at an alkyne terminus successful-
ly constructed both aryl–carbonyl and aryl–aryl axial chirali-
ties with excellent enantio- and diastereoselectivity. Utiliza-
tion of these new axially chiral N,N-dialkylbenzamides for
chiral reagents is currently underway in our laboratory.
Scheme 3. RhI+/binap-catalyzed construction of both aryl–carbonyl and
aryl–aryl axial chiralities.
chiral biarylbenzamide (À)-3ci with excellent enantio- and
diastereoselectivity.[10] The absolute configuration of (À)-3ci
was determined to be (S,S) by the anomalous dispersion
method (Figure 1).[13]
Experimental Section
Typical procedure for Rh-catalyzed [2+2+2] cycloaddition (Table 2,
entry 1): A solution of (S)-segphos (4.6 mg, 0.0075 mmol) in CH2Cl2
(0.5 mL) was added to a solution of [RhCAHTRE(UNG cod)2]BF4 (3.0 mg, 0.0075 mmol)
in CH2Cl2 (0.5 mL) at room temperature, and the mixture was stirred for
5 min. The resulting solution was stirred under H2 (1 atm) at room tem-
perature for 1 h, concentrated to dryness, and dissolved in CH2Cl2
(0.5 mL). To this solution was added
0.165 mmol) in CH2Cl2 (0.5 mL). Then
a
a
solution of 2a (37.2 mg,
solution of 1a (58.3 mg,
0.15 mmol) in CH2Cl2 (1.0 mL) was added dropwise over 5 min at room
temperature. The solution was stirred at room temperature for 1 h. The
resulting solution was concentrated and purified by silica gel chromatog-
raphy (hexane/EtOAc=5:1–2:1), which furnished (À)-3aa (85.1 mg,
0.139 mmol, 92% yield,>99% ee) as a pale yellow oil.
Figure 1. ORTEP drawings of (S,S)-(À)-3ci drawn at the 50% probability
level.
Finally, the rate of racemization of these new axially
chiral N,N-dialkylbenzamides was investigated at 808C in
(CH2Cl)2 (Table 3).[14,15] The effect of the substituents on the
nitrogen center was examined, which revealed that the rates
of racemization of N,N-dimethylamide (3ac, Table 3,
entry 3) and 1-piperidinylamide (3ad, Table 3, entry 4) are
higher than those of N,N-diisopropylamide (3aa, Table 3,
entry 1) and N,N-diethylamide (3ab, Table 3, entry 2). The
effect of the ortho substituents was also examined, which re-
vealed that ortho-(2-methoxypropyl)benzamide (3aa,
Table 3, entry 1) and ortho-(tert-butyl)benzamide (3ae,
Table 3, entry 5) possess highly stable axial chirality, whereas
Acknowledgements
This work was supported partly by a Grant-in-Aid for Scientific Research
(No. 19350046, 20·8746, and 20675002) from the Ministry of Education,
Culture, Sports, Science and Technology, Japan, and The Naito Founda-
tion. We thank Takasago International Corporation for the gift of modi-
fied-BINAP ligands.
Keywords: axial chirality · benzamides · cycloaddition ·
enantioselective catalysis · rhodium
Table 3. Rate of racemization of axially chiral N,N-dialkylbenzamides 3
[(CH2Cl)2, 808C].
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Entry
3
ee [%]
0 h
1 h
6 h
98
98
93
89
>99
91
24 h
1
2
3
4
5
6
7
3aa
3ab
3ac
3ad
3ae
3af
>99
>99
>99
>99
>99
>99
>99
>99
98
98
>99
97
95
93
77
70
97
73
0
3ag
97[a]
76
11
[a]Slight racemization of this compound was observed on storage for
several weeks.
Chem. Eur. J. 2008, 14, 6593 – 6596
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www.chemeurj.org
6595

K. Tanaka et al.
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Received: May 19, 2008
Published online: June 20, 2008
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