Enantioselective synthesis of spirocyclic benzopyranones by rhodium-catalyzed intermolecular [4+2] annulation

Article abstract of DOI:10.1002/anie.200801642

(Chemical Equation Presented) Rounding things off: A cationic Rh ^I/(R,R)-walphos complex catalyzes an enantioselective [4+2] annulation of 2-alkynylbenzaldehydes with cyclic electron-deficient carbonyl compounds at room temperature (see scheme, R³=3,5-(F ₃C)₂C₆H₃, X=C or N). Enantioenriched spirocyclic benzopyranones and isatin derivatives are obtained in high yield (up to 97%) and high enantioselectivity (up to >99%).

Full text of DOI:10.1002/anie.200801642

Communications
DOI: 10.1002/anie.200801642
Synthetic Methods
Enantioselective Synthesis of Spirocyclic Benzopyranones by
Rhodium-Catalyzed Intermolecular [4+2] Annulation**
Daiki Hojo, Keiichi Noguchi, Masao Hirano, and Ken Tanaka*
The hydroacylation of 4-alkenals[1,2] and 4-alkynals[3,4] cata-
lyzed by a cationic rhodium(I)/bisphosphine complex is a
well-established method for the synthesis of cyclopentanones
and cyclopentenones, respectively, in an atom-economical
manner. The hydroacylation of 4-pentenal to give cyclo-
pentanone in high yield via the six-membered rhodacycle A is
catalyzed by a cationic rhodium(I)/1,2-bis(diphenylphosphi-
no)ethane (dppe) complex (Scheme 1).[5] In contrast, the
Scheme 2. Rh-catalyzed dimerizations of 4-alkynals.
benzaldehyde (1a), with various cationic rhodium(I)/bisphos-
phine complexes. Surprisingly, the unexpected dimerization
product 2 was obtained in good yield at room temperature by
using the cationic rhodium(I)/1,4-bis(diphenylphosphino)-
butane (dppb) complex, presumably by an intermolecular
homo-[4+2] annulation between five-membered rhodacycle
C and the carbonyl group of 1a (Scheme 2),[10–12] although no
reaction was observed in the presence of the cationic
rhodium(I)/dppe complex.
A cross-[4+2] annulation of 1a with excess benzaldehyde
(3a, 5 equiv) was investigated in the presence of 10 mol% of
the cationic rhodium(I)/dppb or rhodium(I)/1,1’-bis(diphe-
nylphosphino)ferrocene (dppf) complexes, but the desired
cross-annulation product 4aa was only obtained in low yields
(Table 1, entries 1 and 2).[13] A number of cationic rho-
dium(I)/chiral bisphosphine complexes were screened for
their ability to effect a chemo- and enantioselective cross-
[4+2] annulation (Scheme 3; Table 1, entries 3–11). We were
pleased to find that the use of (R,R)-walphos ((R,R)-10) as a
chiral ligand furnished 4aa in an improved yield with good
enantioselectivity (Table 1, entry 11).
The reaction of 1a with 3a could be carried out using
5 mol% of the Rh catalyst to furnish 4aa with an identical
ee value, while the yield decreased to 31% (Scheme 4). The
amount of carbonyl compound could be reduced to two
equivalents by using electron-deficient ketoester 3b, although
slight erosion of the ee value was observed (Scheme 4).[14]
Fortunately, the reaction of 2-alkynylbenzaldehyde 1a with
only a slight excess of the cyclic electron-deficient carbonyl
compound N-methylisatin (3c) in the presence of 5 mol% of
the cationic rhodium(I)/(R,R)-10 complex proceeded at room
temperature to give the corresponding spirocyclic benzopyr-
anone 4ac in high yield and high enantioselectivity (Table 2,
entry 1).[15,16]
Scheme 1. Rh-catalyzed cyclization and dimerization of 4-alkenals.
reaction of a benzene-linked 4-alkenal, namely 2-vinylbenz-
aldehyde, with the same rhodium catalyst furnishes an
unexpected dimerization product in high yield by an inter-
molecular homo-[4+2] annulation between five-membered
rhodacycle B and the double bond of 2-vinylbenzaldehyde
(Scheme 1).[6–8] The reaction of a 4-alkynal with the cationic
rhodium(I)/dppe complex furnishes a similar dimerization
product in high yield by an intermolecular homo-[4+2] annu-
lation between five-membered rhodacycle C and the triple
bond of the 4-alkynal (Scheme 2).[9] Thus, we examined the
reactions of a benzene-linked 4-alkynal, namely, 2-hexynyl-
[*] D. Hojo, Dr. M. Hirano, Prof. Dr. K. Tanaka
Department of Applied Chemistry
Graduate School of Engineering
Tokyo University of Agriculture and Technology
Koganei, Tokyo 184-8588 (Japan)
Fax: (+81)42-388-7037
E-mail: tanaka-k@cc.tuat.ac.jp
Prof. Dr. K. Noguchi
Instrumentation Analysis Center
Tokyo University of Agriculture and Technology
Koganei, Tokyo 184-8588 (Japan)
[**] This work was partly supported by a Grant-in-Aid for Scientific
Research (No. 19028015) from MEXT Japan and the Kato Memorial
Foundation. We thank Solvias AG for the gift of chiral ferrocenyl
bisphosphine ligands under their University Ligand Kit program. We
also thank Y. Hagiwara for his preliminary experiments.
We then explored the scope of this process with respect to
both 2-alkynylbenzaldehydes and cyclic carbonyl compounds.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200801642.
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Chemie
Table 1: Screening of ligands for the Rh-catalyzed [4+2] annulation of
2-alkynylbenzaldehyde 1a with benzaldehyde (3a).[a]
Table 2: Rh-catalyzed enantioselective [4+2] annulation of 1a–e with
cyclic dicarbonyl compounds 3c–f.[a]
Entry
1 (R)
3
4, yield [%][b], ee [%][c]
Entry
Ligand
Yield [%][b]
ee [%][c]
1
2
1a (nBu)
1b (Cy)
1c (Cl(CH2)3)
1d (Ph)
1e (2-ClC6H4)
3c
3c
3c
3c
3c
(À)-4ac, 95, 93
(À)-4bc, 84, 93
(À)-4cc, 97, 93
(À)-4dc, 96, >99
(À)-4ec, 90, 98
1
2
3
4
5
6
7
8
dppb
dppf
(S,S)-diop
(S,S)-bdpp
(S)-tol-binap
(R,S)-5
(R,S)-6
(R,S)-7
(R,S)-8
28
13
<5
12
23
31
11
23
0
–
–
3[d]
4
<5 (À)
9 (À)
19 (+)
14 (+)
26 (+)
<5 (+)
–
5[e]
9
10
11
(R,R)-9
(R,R)-10
26
47
6 (+)
80 (+)
6
7
1a
1a
3d
3e
(À)-4ad, 96, 92
(À)-4ae, 78, 89
[a] [Rh(ligand)]BF4 (0.010 mmol, 10 mol%), 1a (0.10 mmol), and 3a
(0.50 mmol, 5 equiv) in CH2Cl2 (1.0 mL) were used. [b] Yield of isolated
product. [c] All the ee values were measured by HPLC on chiral stationary
phases.
8
1a (nBu)
1a (nBu)
1b (Cy)
1c (Cl(CH2)3)
1d (Ph)
3 f
3 f
3 f
3 f
3 f
(À)-4af, 77, 93
(À)-4af, 86, 93
(À)-4bf, 87, 92
(S)-(À)-4cf, 77, 94
(À)-4df, 73, 98
9[e]
10[e]
11[e]
12[e]
[a] Reactions were conducted using [Rh((R,R)-10)]BF4 (0.010 mmol,
5 mol%), 1a–e (0.20 mmol), and 3c–f (0.22 mmol, 1.1 equiv) in
CH2Cl2 (2.0 mL) at RT for 18–72 h. [b] Yield of isolated product. [c] All
the ee values were measured by HPLC on chiral stationary phases.
[d] Catalyst: 7.5 mol%. [e] Catalyst: 10 mol%.
Scheme 3. Structures of chiral bisphosphine ligands. Cy=cyclohexyl.
and NH-isatin (3e; Table 2, entry 7) could also participate in
this reaction. Furthermore, acenaphthenequinone (3 f)
reacted with 2-alkynylbenzaldehydes 1a–d in high yields
and high enantioselectivity in the presence of the cationic
rhodium(I)/(R,R)-10 complex, despite its poor solubility in
CH2Cl2 (Table 2, entries 8–12).[17] The absolute configuration
of (À)-4cf was determined to be S by X-ray crystallographic
analysis (Figure 1).[18]
In conclusion, we have developed a cationic rhodium(I)/
(R,R)-walphos-catalyzed highly enantioselective [4+2] annu-
lation of 2-alkynylbenzaldehydes with cyclic electron-defi-
cient carbonyl compounds that leads to enantioenriched
spirocyclic benzopyranones and isatin derivatives.[19] As cyclic
electron-deficient carbonyl compounds (both isatin deriva-
tives and acenaphthenequinone) are commercially available,
and 2-alkynylbenzaldehydes can be prepared in one step by
the Sonogashira coupling of commercially available terminal
alkynes with 2-bromobenzaldehyde, this method serves as an
attractive two-step route to enantioenriched spirocyclic
benzopyranones and isatin derivatives starting from commer-
Scheme 4. Rh-catalyzed enantioselective [4+2] annulation of 1a with
benzaldehyde (3a) and linear dicarbonyl compound 3b.
Both alkyl- (1a and 1b; Table 2, entries 1 and 2) and
chloroalkyl-substituted (1c; Table 2, entry 3) 2-alkynylbenz-
aldehydes reacted with 3c to give the corresponding spirocy-
clic benzopyranones in high yields and high ee values. Not
only alkyl but also phenyl- (1d; Table 2, entry 4) and 2-
chlorophenyl-substituted
(1e;
Table 2,
entry 5)
2-
alkynylbenzaldehydes could participate in this reaction to
give products with higher ee values. With respect to the cyclic
carbonyl compounds, N-phenylisatin (3d; Table 2, entry 6)
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Communications
[4] For reviews, see: a) G. C. Fu in Modern Rhodium-Catalyzed
Organic Reactions (Ed.: P. A. Evans), Wiley-VCH, Weinheim,
2005, p. 79; b) K. Tanaka, J. Synth. Org. Chem. Jpn. 2005, 63, 351.
[5] a) D. P. Fairlie, B. Bosnich, Organometallics 1988, 7, 936; b) D. P.
Fairlie, B. Bosnich, Organometallics 1988, 7, 946.
[6] a) K. Kundu, J. V. McCullagh, A. T. Morehead, Jr., J. Am. Chem.
Soc. 2005, 127, 16042; b) K. Tanaka, D. Hojo, T. Shoji, Y.
Hagiwara, M. Hirano, Org. Lett. 2007, 9, 2059.
[7] For pioneering work on the [4+2] annulation via acylmetal
Figure 1. ORTEP drawing (S)-(À)-4cf drawn at the 50% probability
À
intermediates generated by cleavage of a C C bond of cyclo-
level.
butenediones, see: L. S. Liebeskind, S. L. Baysdon, M. S. South,
J. Am. Chem. Soc. 1980, 102, 7397.
[8] For the [4+2] annulation via acylrhodacylces generated by
cially available reagents. Further expansion of the reaction
scope is currently underway.
À
cleavage of a C C bond of cyclobutanones, see: M. Murakami,
T. Itahashi, Y. Ito, J. Am. Chem. Soc. 2002, 124, 13976.
[9] K. Tanaka, G. C. Fu, Org. Lett. 2002, 4, 933.
À
[10] For examples of carbonyl insertion into a Rh C bond, see: a) C.
Krug, J. F. Hartwig, J. Am. Chem. Soc. 2002, 124, 1674; b) T.
Fujii, T. Koike, A. Mori, K. Osakada, Synlett 2002, 298; c) B.
Bennacer, M. Fujiwara, S.-Y. Lee, I. Ojima, J. Am. Chem. Soc.
2005, 127, 17756; d) J. R. Kong, M. J. Krische, J. Am. Chem. Soc.
2006, 128, 16040; e) K. Tanaka, Y. Otake, A. Wada, K. Noguchi,
M. Hirano, Org. Lett. 2007, 9, 2203; f) K. Tsuchikama, Y.
Yoshinami, T. Shibata, Synlett 2007, 1395.
Experimental Section
Representative procedure (Table 2, entry 1): In an argon atmosphere,
a solution of (R,R)-10 (9.3 mg, 0.010 mmol) in CH2Cl2 (0.3 mL) was
added to a solution of [Rh(cod)2]BF4 (4.1 mg, 0.010 mmol; cod =
cycloocta-l,5-diene) in CH2Cl2 (0.3 mL), and the mixture was stirred
at room temperature for 5 min. H2 was then introduced to the
resulting solution in a Schlenk tube. After stirring the mixture at room
temperature for 1 h, the resulting solution was concentrated to
dryness and dissolved in CH2Cl2 (0.5 mL). A solution of 1a (37.3 mg,
0.200 mmol) and 3c (35.5 mg, 0.220 mmol) in CH2Cl2 (1.5 mL) was
added to this solution, and the mixture stirred at room temperature
for 18 h. The resulting solution was concentrated and purified by
preparative TLC (hexane/EtOAc 4:1), which furnished (À)-4ac
[11] Very recently, we reported the RhI/H8-binap-catalyzed regio-,
diastereo-, and enantioselective [2+2+2] cycloaddition of 1,6-
enynes with electron-deficient ketones, see: K. Tanaka, Y.
Otake, H. Sagae, K. Noguchi, M. Hirano, Angew. Chem. 2008,
120, 1332; Angew. Chem. Int. Ed. 2008, 47, 1312.
[12] For a Rh-catalyzed [4+2] annulation of 4-alkynals with electron-
deficient alkenes, see: a) K. Tanaka, Y. Hagiwara, K. Noguchi,
Angew. Chem. 2005, 117, 7426; Angew. Chem. Int. Ed. 2005, 44,
7260; b) K. Tanaka, Y. Hagiwara, M. Hirano, Eur. J. Org. Chem.
2006, 3582; with isocyanates, see: c) K. Tanaka, Y. Hagiwara, M.
Hirano, Angew. Chem. 2006, 118, 2800; Angew. Chem. Int. Ed.
2006, 45, 2734.
[13] Possible chelation of 2-alkynylbenzaldehyde 1a to the cationic
rhodium center may account for the higher reactivity observed
for 1a compared to benzaldehyde (3a).
(66.5 mg, 0.191 mmol, 95% yield, 93% ee) as
a brown solid.
M.p. 96–978C; [a]2D5 = À52.98 (c = 3.23 gcmÀ3 in CHCl3, 93% ee);
1H NMR (CDCl3, 300 MHz): d = 8.23–8.14 (m, 1H), 7.65 (dt, J = 7.5,
1.2 Hz, 1H), 7.55–7.45 (m, 2H), 7.40 (dt, J = 7.5, 1.2 Hz, 1H), 7.21 (dd,
J = 7.5, 1.2 Hz, 1H), 7.10 (dt, J = 7.5, 0.6 Hz, 1H), 6.88 (d, J = 7.5 Hz,
1H), 5.72 (dd, J = 8.1, 6.3 Hz, 1H), 3.12 (s, 3H), 2.54–2.29 (m, 2H),
1.48–1.18 (m, 4H), 0.86 ppm (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3,
75 MHz): d = 172.2, 163.9, 143.8, 136.4, 134.9, 133.1, 131.0, 129.7,
128.5, 127.8, 126.8, 126.0, 125.7, 125.4, 123.1, 108.8, 84.8, 31.6, 28.8,
[14] The higher reactivity of ketoester 3b than 1a and 3a is
presumably due to its electron-deficient nature and the strong
bidentate coordination of its two carbonyl groups to the cationic
rhodium center.
26.3, 22.2, 13.7 ppm; IR (KBr): n˜ = 3437, 3073, 2928, 1727, 765 cmÀ1
;
HRMS (ESI): calcd for C22H21NO3Na: 370.1419, found: 370.1408
[M+Na]+;
1.0 mLminÀ1
isomer).
CHIRALCEL
tr: 18.5 min (minor isomer) and 30.1 min (major
OD-H,
hexane/2-PrOH
90:10,
,
[15] Synthesis of a chiral spirocyclic compound by the RhI+/H8-binap-
catalyzed enantioselective [2+2+2] cycloaddition of an 1,6-
enyne with N-methylisatin has been reported; see: Ref. [11].
[16] Although the precise mechanism for the high enantioselectivity
and reactivity observed with cyclic dicarbonyl compounds 3c–f is
not clear at the present stage, the rigid bidentate coordination of
their two carbonyl groups to the cationic rhodium center may
construct the rigid chiral environment and enhance the reac-
tivity.
Received: April 8, 2008
Published online: June 23, 2008
Keywords: aldehydes · alkynes · annulation ·
.
asymmetric catalysis · rhodium
[17] Although acenaphthenequinone (3 f) was initially suspended in
CH2Cl2, a clear solution was generated after completion of the
reaction.
[18] CCDC 683327 [(S)-(À)-4cf] contains the supplementary crystal-
lographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[19] Spirocyclic isatin derivatives are found in pharmaceutically
important compounds, see: S. R. Yong, A. T. Ung, S. G. Pyne,
B. W. Skelton, A. H. White, Tetrahedron 2007, 63, 5579, and
references therein.
[1] For pioneering work on the Rh-catalyzed hydroacylation of 4-
alkenals, see: K. Sakai, J. Ide, O. Oda, N. Nakamura, Tetrahedron
Lett. 1972, 13, 1287.
[2] For reviews, see: a) K. Sakai, J. Synth. Org. Chem. Jpn. 1993, 51,
733; b) B. Bosnich, Acc. Chem. Res. 1998, 31, 667; c) M. Tanaka,
K. Sakai, H. Suemune, Curr. Org. Chem. 2003, 7, 353.
[3] For pioneering work on the Rh-catalyzed hydroacylation of 4-
alkynals, see: K. Tanaka, G. C. Fu, J. Am. Chem. Soc. 2001, 123,
11492.
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