Asymmetric semipinacol rearrangement of 2,3-allenols with N-bromo-1,8-naphthalimide

Article abstract of DOI:10.1039/c4cc00767k

A method using quinidine and optically active binol-derived phosphoric acid as a cocatalyst to catalyze the asymmetric semipinacol rearrangement of 2,3-allenols forming optically active 3-bromo-3-enals that contain an all-carbon quaternary stereocenter ha

Full text of DOI:10.1039/c4cc00767k

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Asymmetric semipinacol rearrangement of
2,3-allenols with N-bromo-1,8-naphthalimide†
Cite this: Chem. Commun., 2014,
50, 4445
Binjie Guo, Chunling Fu* and Shengming Ma*
Received 28th January 2014,
Accepted 25th February 2014
DOI: 10.1039/c4cc00767k
www.rsc.org/chemcomm
Table 1 Optimization of the asymmetric reaction between allenol 1a and 2a
A method using quinidine and optically active binol-derived phos-
phoric acid as a cocatalyst to catalyze the asymmetric semipinacol
rearrangement of 2,3-allenols forming optically active 3-bromo-3-
enals that contain an all-carbon quaternary stereocenter has been
developed. After some further treatments, the products with practical
enantiomeric purity could be prepared.
One of the most challenging topics in modern organic synthesis is
asymmetric construction of chiral quaternary all-carbon stereocen-
ters, and it has always been in high demand for the development
of synthetic methodologies.1 In our previous work,2 we showed
that 3-halo-3-enals or 2-halo-2-alkenyl ketones that contain an
a-quaternary all carbon stereocenter may be formed by the electro-
philic addition/1,2-shift of 2,3-allenols with X+ (X = Br, I). We
hypothesized that the semipinacol rearrangement of allenols could
also be asymmetrically catalyzed to afford chiral 3-halo-3-enals that
contain a quaternary all-carbon stereocenter3,4 (Scheme 1).
Isolated yield ee of R-3ab
Entry Catalyst
Acid
t (h) of R-3a (%)
(%)
1
2
3
4
5
6
7
8
(DHQD)2PYR
—
—
—
—
—
7
17
71
80
ꢀ8
7
5
(DHQD)2PHAL
(DHQD)2PYDZ
(DHQD)2AQN
Quinidine (20%)
Quinidine (20%) (R)-4a
—
13.5 82
14.7 60
6
12
79
2.3 81
(R)-4a 26 53
21
37
0
Quinine (20%)
(S)-4a 11
92
ꢀ30
a
All reactions were performed with 0.1 mmol of 1a in 2 mL of toluene
unless otherwise noted. Determined by HPLC analysis using a chiral
stationary phase.
b
the catalyst. And to our delight, the enantioselectivity was increased
to 21% ee with a yield of 79% (Table 1, entry 5). According to the
literature, the use of chiral phosphoric acid as a cocatalyst may
dramatically enhance the stereochemical control of cinchona alkaloid
derivatives.7 So (R)-(ꢀ)-1,10-binaphthyl-2,20-diyl hydrogen phosphate
(R-4a) was added as a cocatalyst. In fact, the enantiomeric excess was
improved to 37% ee with a yield of 81% (Table 1, entry 6). What’s
more, R-4a only gave racemic 3a in the absence of quinidine (Table 1,
entry 7). Quinine in the presence of S-acid (S-4a) gave a yield of 92%
and ꢀ30% ee (Table 1, entry 8).
Scheme 1 Asymmetric semipinacol rearrangement of 2,3-allenols.
In our initial study, 1-(4-methoxylphenyl)-2-butyl-2,3-allenol 1a
was used as a model substrate with N-bromo-1,8-naphthalimide 25
as X+ sources. We chose the commonly used cinchona alkaloid
derivatives, such as (DHQD)2PYR, (DHQD)2PHAL, (DHQD)2PYDZ
and (DHQD)2AQN6 as catalysts. But to our disappointment, only
very low enantiomeric selectivity (o10% ee) was observed (Table 1,
entries 1–4). Then, we just used the simplest quinidine as
Then, other chiral-binol-derived phosphoric acids were examined.
As we can see, when iodo-substituted acid (4b) was used, the ee value
could be improved to 50% (Table 2, entry 1). A much better ee of 72%
was achieved when phenyl-substituted acid (4c) was used (Table 2,
entry 2). Further optimization on the phenyl group, such as the bulky
t-butyl group (4d), the electron-donating group (4-MeO (4e), 4-Me (4f)),
the electron-withdrawing group (4-CF3, 4g) and 4-phenyl (4h)
Laboratory of Molecular Recognition and Synthesis, Department of Chemistry,
Zhejiang University, Hangzhou, 310027, Zhejiang, P. R. China.
E-mail: masm@sioc.ac.cn; Fax: +86-21-6416-7510
† Electronic supplementary information (ESI) available: CCDC 980926. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c4cc00767k
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gave no better results (Table 2, entries 3–7). When the 2-naphthyl with a yield of 80% and 71% ee (Table 3, entry 11). Interestingly, it was
(4i) or the 9-anthryl (4j) group was introduced instead of the phenyl observed that with the parent phenyl (1l) group, the result was rather
group, we observed 53% ee and 30% ee, respectively (Table 2, poor with only 8% ee of 3l (Table 3, entry 12).
entries 8 and 9). When the styryl (4k) group was introduced, the ee
Table 3 The scope of the asymmetric semipinacol rearrangement of allenola
value dropped to 48% with a yield of 75% (Table 2, entry 10).
Alcohols have been used as additives in some reports,3g due to the
possible formation of the hydrogen bond enhancing the stereo-
selectivity of the catalyst. To our delight, we found that the addition
of 10 mol% of MeOH could slightly improve the ee value to 74%
and gave a yield of 82% even with 15 mol% of quinidine and
5 mol% of R-phenyl-acid (4c) (Table 1, entry 11). Other conditions
such as solvent effect, temperature, the ratio of catalysts, additives
and X+ sources have also been screened (see ESI†), but no better
results were achieved.
Entry
R
t (h)
Yield of R-3b (%)
ee of R-3c (%)
1
2
3
4
5
6
7
8
n-Bu (1a)
Et (1b)
3.2
2.5
3
4.2
2.5
4
3
3
3
11.5
3
75 (3a)
77 (3b)
83 (3c)
87 (3d)
85 (3e)
83 (3f)
70 (3g)
98 (3h)
78 (3i)
75 (3j)
80 (3k)
59 (3l)
75
77
77
73
72
73
66
64
76
78
71
8
n-C3H7 (1c)
n-C5H11 (1d)
n-C6H13 (1e)
n-C10H21 (1f)
i-Pr (1g)
c-C6H11 (1h)
Allyl (1i)
Bn (1j)
Ph(CH2)3 (1k)
Ph (1l)
Table 2 Optimization of the asymmetric semipinacol rearrangement of
allenol 1aa
9
10
11
12d
3
a
All reactions were performed with 0.5 mmol of 1 in 10 mL of toluene
b
c
unless otherwise noted. Yield of an isolated product. Determined by
HPLC analysis using a chiral stationary phase. The reaction was
Entry
R
t (h) Yield of R-3ab (%) ee of R-3ac (%)
d
conducted on a 0.2 mmol scale of 1l.
1
2
3
4
5
6
7
8
I (4b)
Ph (4c)
11.5
12.3
3.8
3.7
4.8
16
81
80
85
88
76
75
89
88
81
75
82
73
68
50
72
59
33
59
60
43
53
30
48
74
27
8
4-t-BuC6H4 (4d)
4-MeOC6H4 (4e)
4-MeC6H4 (4f)
4-CF3C6H4 (4g)
4-PhC6H4 (4h)
2-Naphthyl (4i)
9-Anthryl (4j)
Styryl (4k)
Ph (4c)
It is interesting to observe that the electronic nature of the
aryl group may also influence the enantioselectivity of the reaction:
1-(4-ethoxyl)phenyl substituted allenol (1m) gave almost the same
results: 80% yield and 73% ee (Table 4, entry 1); allenol 1n with the
3,4-methylenedioxyphenyl group on the 1-position gave a yield of
65% and a little lower 62% ee (Table 4, entry 2); it is worth noting
that a heteroaryl such as 2-thienyl substituted allenol 1o may also
afford the product in 73% yield and 68% ee under the standard
reaction conditions (Table 4, entry 3). However, when the aryl group
was replaced with the 4-MeC6H4 (1q) group, both the yield and ee of
the products dropped (Table 4, entry 5).
13
3.7
4.3
11
3
2.7
1
9
10
11d
12d,e
13d,f
14d,g
Ph (4c)
Ph (4c)
Ph (4c)
25
B75
53
a
All reactions were performed with 0.1 mmol of 1a in 2 mL of toluene
b
c
unless otherwise noted. Yield of an isolated product. Determined by
HPLC analysis using a chiral stationary phase. 15 mol% of quinidine,
5 mol% of 4c and 10 mol% of MeOH were used. NBS was used instead
of 2. 1,3-Dibromohydantoin was used instead of 2. The reaction was
conducted at ꢀ30 1C.
d
e
f
g
Table 4 The scope of the asymmetric semipinacol rearrangement of allenola
With the optimized reaction conditions in hand, we studied the
scope of this reaction with the typical results summarized in Table 3.
Allenols with alkyl groups on the 2-position mostly gave an ee value
over 70%. For example, when the ethyl group (1b) was introduced,
3b was produced with a yield of 77% and 77% ee (Table 3, entry 2).
Propyl (1c), pentyl (1d), hexyl (1e) and decyl (1f) substituted allenols
gave 83–87% yields and 72–77% ee (Table 3, entries 3–6). For
secondary alkyl groups, probably due to the steric effect, iso-propyl
(1g) and cyclohexyl (1h) substituted allenols gave the products with
lower ee values of 66% and 64%, respectively (Table 3, entries 7 and 8).
To our delight, when the allyl group (1i) was introduced, 3i was
afforded with a yield of 78% and 76% ee: no reaction occurred to the
allylic CQC bond (Table 3, entry 9). When the benzyl group (1j) was
introduced, 3j was afforded with a yield of 75% and 78% ee (Table 3,
entry 10), while 2-(3-phenylpropyl) substituted enal (3k) was afforded
Yield of
ee of
Entry Ar
R
t (h) R-3b (%) R-3c (%)
1
2
3
4
5
4-EtOC6H4 (1m)
3,4-OCH2OC6H3 (1n)
2-Thienyl (1o)
3,4,5-(MeO)3C6H2 (1p) Et
4-MeC6H4 (1q) n-Bu
n-Bu
n-Bu
n-Bu
3.3
3.3
3
16.7
5.5
80 (3m)
65 (3n)
73 (3o)d
61 (3p)
54 (3q)
73
62
68
61
54
a
All reactions were performed with 0.5 mmol of 1 in 10 mL of toluene
b
c
unless otherwise noted. Yield of an isolated product. Determined by
d
HPLC analysis using a chiral stationary phase. The absolute configu-
ration of 3o is S according to the sequence rule.
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It is worth noting that after recrystallization8 from the solution real identity of the catalyst has not been established. Due to the
of CH2Cl2 and n-hexane three times, the ee value of 3k reached 99% easy availability of the allenols, the catalysts, and the potential
(17% yield). The absolute configuration of 3k was determined by of the highly functionalized aldehydes, this method will be of
the X-ray diffraction study9 (Fig. 1). A large scale reaction of 1k high interest to the community. Further study on this reaction
(882.5 mg, 3.0 mmol) was also conducted and the ee value of 3k is being actively pursued in this laboratory.
reached 94% after twice recrystallization with 40% yield (for details,
see the ESI†).
Financial support from the National Basic Research Program of
China (2011CB808700) and the National Nature Science Founda-
tion of China (21232006) is greatly appreciated. Shengming Ma is a
Qiu Shi Adjunct Professor at the Zhejiang University. We thank
Miss Qiong Yu in this group for reproducing the results presented
in Table 3, entries 2 and 9, and entry 2 in Table 4.
Notes and references
Fig. 1 X-ray diffraction study of R-3k.
1 Quaternary Stereocenters: Challenges and Solutions for Organic Synthesis,
ed. J. Christoffers and A. Baro, Wiley-VCH, Weinheim, Germany, 2005.
For recent reviews on the asymmetric formation of quaternary carbon
centers, see: (a) C. J. Douglas and L. E. Overman, Proc. Natl. Acad. Sci.
U. S. A., 2004, 101, 5363; (b) B. M. Trost and C. Jiang, Synthesis, 2006,
369; (c) P. G. Cozzi, R. Hilgraf and N. Zimmermann, Eur. J. Org. Chem.,
2007, 5969; (d) M. Bella and T. Gasperi, Synthesis, 2009, 1583.
2 (a) C. L. Fu, J. Li and S. M. Ma, Chem. Commun., 2005, 4119–4121;
(b) J. Li, C. L. Fu, G. Chen, G. Chai and S. M. Ma, Adv. Synth. Catal.,
2008, 350, 1376–1382.
3 For recent articles on the formation of quaternary carbon stereocenters via
semipinacol rearrangement see: (a) B. M. Trost and T. Yasukata, J. Am.
Chem. Soc., 2001, 123, 7162; (b) B. M. Wang, L. Song, C. A. Fan, Y. Q. Tu
and W. M. Chen, Synlett, 2003, 1497–1499; (c) M. Wang, B. M. Wang,
L. Shi, Y. Q. Tu, C. A. Fan, S. H. Wang, X. D. Hu and S. Y. Zhang, Chem.
Commun., 2005, 5580–5582; (d) F. Kleinbeck and F. D Toste, J. Am. Chem.
Soc., 2009, 131, 9178; (e) E. Zhang, C. A. Fan, Y. Q. Tu, F. M. Zhang and Y. L
Song, J. Am. Chem. Soc., 2009, 131, 14626; ( f ) Q. W. Zhang, C. A. Fan,
H. J. Zhang, Y. Q. Tu, Y. M. Zhao, P. M. Gu and Z. M. Chen, Angew. Chem.,
Int. Ed., 2009, 48, 8572; (g) Z. M. Chen, Q. W. Zhang, Z. H. Chen, H. Li,
Y. Q. Tu, F. M. Zhang and J. M. Tian, J. Am. Chem. Soc., 2011, 133,
8818–8821; (h) H. Li, F. M. Zhang, Y. Q. Tu, Q. W. Zhang, Z. M. Chen,
Z. H. Chen and J. Li, Chem. Sci., 2011, 2, 1839–1841; (i) C. H. Muller,
M. Wilking, A. Ruhlmann, B. Wibbeling and U. Henneche, Synlett, 2011,
2043; ( j) Z. M. Chen, B. M. Yang, Z. H. Chen, Q. W. Zhang, M. Wang and
Y. Q. Tu, Chem.–Eur. J., 2012, 18, 12950–12954.
To demonstrate the practicality of this reaction, another gram-
scale reaction of 1c was further conducted. The reaction of 1c
(1.0908 g, 5.0 mmol) with 2 afforded the corresponding product 3c
(1.1428 g) with a yield of 77% and 74% ee. Further treatment of 3c
with 2,4-dinitrophenylhydrazine in the mixed solution of EtOH and
H2O catalyzed by H2SO4 (98%) gave hydrazone 5c in a yield of 92%
and 75% ee. After crystallization from the solution of CH2Cl2 and
n-hexane, the crystals (7% ee, 19% yield) were removed and
evaporation of the mother liquid gave the optically active enantio-
mer with 99% ee (72% yield), which was then dried, and sub-
sequently stirred in the solution of dioxane with concentrated
hydrochloric acid (12 M) at 50 1C for 17.7 h to afford enal R-3c
in a yield of 81% and 98% ee (Scheme 2).
4 (a) F. Romanov-Michailidis, L. Guenee and A. Alexakis, Angew. Chem.,
Int. Ed., 2013, 52, 9266–9270; (b) F. Romanov-Michailidis, L. Guenee
and A. Alexakis, Org. Lett., 2013, 15, 5890; (c) B. Alcaide, P. Almendros,
A. Luna, S. Cembellin, M. Arno and L. R. Domingo, Chem.–Eur. J., 2011,
17, 11559; (d) B. Alcaide, P. Almendros, A. Luna and M. R. Torres, Adv.
Synth. Catal., 2010, 352, 621.
5 Compound 2 was synthesized according to the literature: S. Fujisaki,
S. Hamura, H. Eguchi and A. Nishida, Bull. Chem. Soc. Jpn., 1993, 66,
2426–2428.
6 (a) K. B. Sharpless, W. Amberg, Y. L. Bennani, G. A. Crispino, J. Hartung, K. S.
Jeong, H. L. Kwong, K. Morikawa, Z. M. Wang, D. Q. Xu and X. L. Zhang,
J. Org. Chem., 1992, 2768–2771; (b) G. A. Crispino, K. S. Jeong, H. C. Kolb,
Z. M. Wang, D. Q. Xu and K. B. Sharpless, J. Org. Chem., 1993, 3785–3786.
7 (a) J. W. Xie, X. Huang, L. P. Fan, D. C. Xu, X. S. Li, H. Su and
Y. H. Wen, Adv. Synth. Catal., 2009, 351, 3077–3082; (b) G. Bergonzini,
S. Vera and P. Melchiorre, Angew. Chem., 2010, 122, 9879–9882 (Angew.
Chem., Int. Ed., 2010, 49, 9685–9688); (c) X. Tian, C. Cassani, Y. Liu,
A. Moran, A. Urakawa, P. Galzerano, E. Arceo and P. Melchiorre, J. Am.
Chem. Soc., 2011, 133, 17934–17941; (d) O. Lifchits, M. Reisinger and
B. List, J. Am. Chem. Soc., 2010, 132, 10227–10229; (e) J. Song, C. Guo,
A. Adele, H. Yin and L. Gong, Chem.–Eur. J., 2013, 19, 3319–3323.
8 W. L. F. Armarego and C. L. L. Chai, Purification of Laboratory Chemicals,
Elsevier Inc., 5th edn, 2003, pp. 14–17ISBN: 978-0-7506-7571-0.
9 Crystal data for compound 3k: C20H21BrO2, MW = 373.28, Monoclinic,
space group P21, final R indices [I 4 2s(I)], R1 = 0.0472, wR2 = 0.0921,
R indices (all data) R1 = 0.0723, wR2 = 0.1047, a = 10.7903 (11) Å,
b = 8.3733 (5) Å, c = 10.8570 (9) Å, a = 901, b = 110.884 (10)1, g = 901,
V = 916.49(13) Å3, T = 293 (2) K, Z = 2, reflections collected/unique:
6043/2460 (Rint = 0.0344), number of observations [42s(I)] 3325,
parameters: 209. CCDC 980926.
Scheme 2 Preparation of R-3c with 98% ee.
In conclusion, we have developed a method using quinidine
and chiral-binol-derived phosphoric acid as a cocatalyst to catalyze
the asymmetric semipinacol rearrangement of 2,3-allenols forming
chiral 3-bromo-3-enals that contain a quaternary all-carbon
stereocenter. With further treatments, the 3-bromo-3-enals with
practical enantiomeric excess may be prepared. However, the
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 4445--4447 | 4447