Catalytic intermolecular carbon electrophile induced semipinacol rearrangement

Article abstract of DOI:10.1039/c2cc38585f

A catalytic intermolecular carbon electrophile induced semipinacol rearrangement was realized and the asymmetric version was also preliminarily accomplished with 92% and 82% ee. The complex tricyclic system architecture with four continuous stereogenic centers could be achieved from simple starting materials in a single step under mild conditions. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c2cc38585f

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Catalytic intermolecular carbon electrophile induced
semipinacol rearrangement†
Cite this: Chem. Commun., 2013,
49, 1648
Qing-Wei Zhang, Xiao-Bo Zhang, Bao-Sheng Li, Kai Xiang, Fu-Min Zhang,
Shao-Hua Wang and Yong-Qiang Tu*
Received 29th November 2012,
Accepted 7th January 2013
DOI: 10.1039/c2cc38585f
www.rsc.org/chemcomm
A catalytic intermolecular carbon electrophile induced semipinacol importance of forming multiple bonds and complex molecules in a
rearrangement was realized and the asymmetric version was also single step without the need for the synthesis of complex substrates,7
preliminarily accomplished with 92% and 82% ee. The complex the intermolecular semipinacol rearrangements as a beneficial
tricyclic system architecture with four continuous stereogenic centers complement to the intramolecular ones are still highly desirable.
could be achieved from simple starting materials in a single step under
mild conditions.
As a long standing research interest of our group, we have
recently engaged in the enantioselective non-carbocation partici-
pated semipinacol rearrangement of the activated allylic alcohol
Intramolecular carbon electrophile induced semipinacol rearrange- such as enol ether and enamide which renders the alkene more
ment (Prins-pinacol reaction) has been extensively studied as one of basic and nucleophilic (X = N, O, Scheme 1).8,9 Although the
the powerful C–C bond forming reactions.1,2 This tandem process substrate is highly sensitive to acid as stated above,10 based on
initiated by the in situ formed stabilized carbocations is a practical these successful results, we envisioned that such a type of double
protocol for the construction of complex molecular architectures bond might react with a carbon electrophile (E = C, Scheme 1) to
through simple operation.3 As a result, many elegant total syntheses effect an intermolecular semipinacol rearrangement. Herein, we
of natural products have also been accomplished using this strategy wish to present our preliminary results on this subject.2a,b
as a key step.4 Accordingly, the intermolecular ones are also impor-
Initially, 1a and the electrophile ethyl glyoxalate 2a were selected
tant in terms of generating the complexity, diversity and especially to verify the designed reaction (Table 1). When the non-protected
chirality of the product from a simple prochiral substrate. However, substrate 1a was subjected to the reaction conditions using DCM as
due to the inherent low electrophilicity of carbon electrophiles solvent and Cu(OTf)2 as a catalyst, only the direct semipinacol
compared with heteroatom ions, it was challenging for the semi- rearrangement product of 1a was isolated leaving 2a untouched
pinacol substrate (or motif) to survive under the harsh conditions (entry 1). We found that the protecting group of 1a was critical for
such as stoichiometric strong Lewis acid (Scheme 1). Even though the performance of the reaction (entries 2–6). Thus 1b with TBS
many formal intermolecular carbon electrophile induced (Prins- protecting group was then attempted for screening of the reaction
pinacol) semipinacol reactions have been disclosed through the conditions (entries 2–15). When toluene was employed, the
preformation of hemiacetal,5 examples of clear-cut intermolecular expected reaction took place which was followed by ketalization
reaction are rarely reported and the catalytic asymmetric version of reaction to afford tricyclic compound 3b in 52% yield with 51 : 1 dr
these transformations has not been reported.6 Therefore, given the (entry 2). However, under similar conditions in DCM, only trace
amounts of 3a could be detected (entry 3) and the result was even
worse when the reaction was carried out in more polar solvent
nitromethane (entry 4). Further screening showed that acetone was
a promising solvent from which 3b could be isolated in 42% yield
but with a decreased dr of 10 : 1 (entry 5). The coordinating solvent
THF was much better and the reaction proceeded readily to give 3b
Scheme 1 Different electrophiles induced semipinacol rearrangement.
in 64% yield and an excellent dr of >100 : 1 (entry 6).
The catalyst was also important for the performance of the
reaction. For example, (CuOTf)PhH1/2 could give a comparable yield
of 51% albeit with a decreased dr of 43 : 1 (entry 7). While strong
Lewis acid Sc(OTf)3 or In(OTf)3 could only give low yields (B10%)
State Key Laboratory of Applied Organic Chemistry and Department of Chemistry,
Lanzhou University, Lanzhou 730000, P. R. China. E-mail: tuyq@lzu.edu.cn;
Fax: +86 931 8912582
† Electronic supplementary information (ESI) available. CCDC 890030 (3a) and
and poor dr (B1 : 1) (entries 8 and 9). On the other hand, the
890031 (3hb). For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c2cc38585f
relatively weak Lewis acids such as LaCl3, ZnBr2, MgBr2 and AgOTf
c
1648 Chem. Commun., 2013, 49, 1648--1650
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Table 1 Optimization of the reaction conditionsa
Table 2 Substrate scopea
Cat. (10 mol%) Time (h) Yieldb (%) drc
Entry Substrate
Productb (dr)
Yieldc (%)
Entry Solvent
1
2
3
4
5
6
7
8
DCM
Toluene
DCM
CH3NO2 Cu(OTf)2
Acetone
THF
THF
THF
THF
THF
THF
THF
THF
THF
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
0.5
2
0.5
0.5
0.5
4
nd
52
Trace
nd
42
64
51
—
51 : 1
1e
—
—
1b R = TBS
1c R = TMS 3a R = H (a : b 5 : 1)
3b R = TBS (a : b 100 : 1)
79
85
Cu(OTf)2
Cu(OTf)2
(CuOTf)PhH1/2
Sc(OTf)3
In(OTf)3
LaCl3
10 : 1
2
3
>100 : 1
43 : 1
1.1 : 1
1.2 : 1
—
—
—
—
>100 : 1
11 : 1
4
0.5
0.5
4
4
4
4
4
0.5
13
9
9
10
11
12
13
14d
15d,e
nd
Trace
nd
nd
79f
93
3c (a : b 5 : 1) 71% 3c0 20%
91
42
1d
1e
ZnBr2
MgBr2ꢁEt2O
AgOTf
4d
Cu(OTf)2
Cu(OTf)2
Acetone
3d (a : b >10 : 1)
a
Reaction conditions: 1b (1a for entry 1) (0.1 mmol), 2 (0.2 mmol),
b
catalyst (0.01 mmol), 100 mg 5 Å molecular sieves at rt. Isolated yield.
c
d
dr of a : b, determined by 1H NMR. Addition of 1b was performed
e
5
using a syringe pump for 1 h. The reaction was performed at ꢀ10 1C.
f
Yield of 3a after being treated with HF (aq.).
Et, 3ea : 3e0 78% (8 : 1), 3eb 16%
94
1g
1g (1.0 g)
1h
6
7
Et, 3ea : 3e0 81% (13 : 1), 3eb 15% 96
tBu, 3fa : 3f0 67% (9 : 1), 3fb 17%
84
were ineffective (entries 10–13). To further prevent the decomposi-
tion and direct semipinacol rearrangement of the substrate, slow
addition of 1b using a syringe pump was performed. Deprotected
product 3a along with 3b was observed in this case. The reaction
mixture finally gave 3a in 79% yield without erosion of dr after being
treated with aqueous HF (entry 14). Similarly, up to 93% yield could
be gained with 11 : 1 dr at ꢀ10 1C in acetone (entry 15). These
results above demonstrated the challenge of this tandem reaction
which requires appropriate selection of each reaction parameter. It
should be noted that other diastereomers were not detected in the
above evaluation and the relative configuration of 3a was unam-
biguously determined by X-ray crystallography.11
The substrate scope was then studied based on the above
optimization (using Cu(OTf)2 as a catalyst, THF or acetone as
solvent, Table 2). As shown with 1c, the variation of the protecting
group from TBS to TMS gave a slightly increased yield of 85% and a
lower dr of 5 : 1 (entry 2). Unlike the dihydropyran substrate 1b and
1c, the dihydrofuran substrate 1d could also generate cis semipi-
nacol rearrangement product 3c0 in 20% yield, which could not
undergo further ketalization reaction (entry 3).12 A total yield of
91% was obtained together with the normal product 3c (71% yield).
Cyclopentanol type substrate 1e, which proved to be problematic in
the Brønsted acid catalyzed asymmetric semipinacol rearrange-
ment in our previous study,7a underwent smooth transformation
at ꢀ10 1C to form hemiketal 3d instead of the ketal counterpart in
42% yield and with relatively high dr (>10 : 1, entry 4) compared
with substrates with cyclobutanol and cyclopropanol groups.12 The
dihydropyrrole counterparts 1g and 1h were also amenable to this
protocol to give the products in good to excellent yields of
84%–96% (entries 5–7). The gram scale synthesis was performed
with satisfactory results (entry 6), and a similar good result was
obtained when t-butyl glyoxalate 2b was used instead of 2a as
an electrophile (entry 7). In these cases (entries 5–7), the cis
a
1 (0.2 mmol except for entry 6), 2a (2.0 equiv., 2b for entry 7), Cu(OTf)2
(10 mol%), THF (2 mL) and 5 Å molecular sieves (200 mg) were stirred
at rt. Isolated yield, dr (3a : 30 unless noted) confirmed by 1H NMR.
b
c
d
Combined isolated yield. Acetone was used instead of THF, the
e
reaction was performed at ꢀ10 1C. A syringe pump was used.
semipinacol rearrangement products (3e0–3f0) were also observed
as minor isomers in 8 : 1, 13 : 1, 9 : 1 ratios, respectively, which
were inseparable with 3ea or 3fa.
Subsequently, as shown in Table 3, the three-component reac-
tions involving additional aromatic amines 4 were also tested using
the procedure described in the footnote (also see ESI†). A good
result was also obtained, giving 3g–3i in 54–76% yield in acetone
(entries 1–3).13 However, only low dr values (a : b) could be gained
(B1 : 1) for 3g–3i and the cis semipinacol rearrangement products
(3g0–3i0) also emerged (9 : 1, 11 : 1, 13 : 1 ratios with 3ga–3ia). In
contrast, when substrate 1g was introduced with 4b in THF instead
of acetone, the major isomer was obtained in 83% yield together
with other isomers which lack the stability to be verified (entry 4).
The relative configuration of the minor diastereomer 3hb was also
determined by X-ray crystallography which is consistent with the
two component reaction.11
In order to facilitate this transformation’s future applications,
the asymmetric version of this tandem reaction was attempted
(Scheme 2). Subsequently, 1g was selected as the substrate and
subjected to the catalytic asymmetric carbon electrophile induced
semipinacol rearrangement reaction.14 When the reaction was
performed in the presence of 15 mol% Cu(OTf)2 using (S,S)-t-
BuBOX (15 mol%) as a ligand, the desired products 3ea and 3eb
could also be obtained in respective 79%, 20% yield and 91% ,
82% ee, indicating the efficiency of the enantioselective reaction.15
In conclusion, the catalytic intermolecular carbon electro-
phile induced semipinacol rearrangement was realized. The
c
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Table 3 Three component reactionsa
Notes and references
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Ene Reactions, ed. B. M. Trost, I. Fleming and C. H. Heathcock,
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3 For selected examples, see: (a) P. Martinet, G. Mousset and M. C. R.
Colineau, C. R. Seances Acad. Sci., Ser. C, 1969, 268, 1303;
(b) M. H. Hopkins and L. E. Overman, J. Am. Chem. Soc., 1987,
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118, 12541; (d) A. Armstrong and S. E. Shanahan, Org. Lett., 2005, 7, 1335;
(e) M. A. Lavigne, M. Riou, M. Girardin, L. Morency and L. Barriault, Org.
Entry
1
Substrate
Productb (dr)
Yieldc (%)
1b
4a (R1 = NO2
R2 = H)
3ga : 3g0 40% (9 : 1), 3gb 36%
76
1b
2
3
4a (R1 = NO2
R2 = Br)
´
Lett., 2005, 7, 5921; ( f ) M.-A. Beaulieu, K. C. Guerard, G. Maertens,
C. Sabot and S. Canesi, J. Org. Chem., 2011, 76, 9460.
4 (a) O. Corminboeuf, L. E. Overman and L. D. Pennington, J. Am.
Chem. Soc., 2003, 125, 6650; (b) A. Armstrong, Y. Bhonoah and
S. E. Shanahan, J. Org. Chem., 2007, 72, 8019; (c) M. A. Beaulieu,
3ha : 3h0 35% (11 : 1), 3hb 32%
67
54
´
C. Sabot, N. Achache, K. C. Guerard and S. Canesi, Chem.–Eur. J.,
1b
4c (R1 = CF3
R2 = H)
´
2010, 16, 11224; (d) M.-A. Beaulieu, K. C. Guerard, G. Maertens,
C. Sabot and S. Canesi, J. Org. Chem., 2011, 76, 9460; (e) Z.-H. Chen,
Y.-Q. Tu, S.-Y. Zhang and F.-M. Zhang, Org. Lett., 2011, 13, 724.
5 (a) N. Hanaki, J. T. Link, D. W. C. MacMillan, L. E. Overman,
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Chem., Int. Ed., 2012, 51, 5367, and references therein.
3ia : 3i0 31% (13 : 1), 3ib 23%
4d
6 (a) I. L. Lysenko, H.-S. Oh and J. K. Cha, J. Org. Chem., 2007, 72, 7903;
´
(b) A. M. Meyer, C. E. Katz, S.-W. Li, D. V. Velde and J. Aube, Org.
1g and 4b
X = NTs, 3j
83
Lett., 2010, 12, 1244; (c) R. J. Phipps, L. McMurray, S. Ritter,
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a
To an oven dried Schlenk tube was added 2 (2.0 equiv.), 5 Å molecular sieves
(1 g), aniline derivatives 4 (1.0 equiv.), Cu(OTf)2 (2 mol%) and acetone (5 mL).
Addition of 1b (1.0 mmol in 5 mL acetone) to the system was then performed
using a syringe pump for 1 h at room temperature. b Isolated yield, dr
(3a : 30) confirmed by 1H NMR. c Combined isolated yield. d 0.2 mmol scale
in THF with a 15 mol% catalyst, without using a syringe pump.
9 (a) L. A. Paquette, D. E. Lawhom and C. A. Teleha, Heterocycles, 1990,
30, 765; (b) M. D. B. Fenster, B. O. Patrick and G. R. Dake, Org. Lett.,
2001, 3, 2109.
10 However, examples of carbon electrophile induced other types of
tandem reactions without introducing the liable semipinacol sub-
Scheme 2 Catalytic enantioselective intermolecular carbon electrophile
´
strate were reported: (a) O. Jimenez, G. de la Rosa and R. Lavilla,
induced semipinacol rearrangement.
Angew. Chem., Int. Ed., 2005, 44, 6521; (b) K. B. Bahnck and
S. D. Rychnovsky, J. Am. Chem. Soc., 2008, 130, 13177;
(c) A. K. Ghosh, C. D. Martyr and C.-X. Xu, Org. Lett., 2012,
14, 2002; (d) P. Borkar, P. van de Weghe, B. V. Subba Reddy,
complex tricyclic system architecture with four continuous stereo-
genic centers could be achieved from simple starting materials
under mild conditions. The enantioselective version was also
developed with excellent results. We believe that this reaction
would find its extensive applications in organic synthesis. Further
development and improvement of the reaction and its applications
in total synthesis is currently underway.
We gratefully acknowledge financial support from the NSFC (No.
21072085, 20921120404, 21102061, 20972059, 21202073, 21290180
and 21272097), ‘‘973’’ program of 2010CB833203, Key National S&T
Program ‘‘Major New Drug Development’’ of Ministry of Health of
China (2012ZX09201101-003), ‘‘111’’ program of MOE, and scholar-
ship award for excellent doctoral student of MOE (86007). We also
thank Professor Chun-An Fan for insightful discussions.
´
J. S. Yadav and R. Gree, Chem. Commun., 2012, 48, 9316.
11 Crystallographic data for 3a, 3hb have been deposited at the
Cambridge Crystallographic Data Centre (deposition no. CCDC
890030 (3a); 890031 (3hb))†.
12 In our study, the cis semipinacol rearrangement product 30 was
detected as one isomer, for similar results see ref. 6.
13 Complex mixtures were observed in THF for entries 1–3, Table 3.
14 For selected examples of related asymmetric Prins and ene reactions,
see: (a) H.-K. Luo, Y.-L. Woo, H. Schumann, C. Jacob, M. van Meurs,
H.-Y. Yang and Y.-T. Tan, Adv. Synth. Catal., 2010, 352, 1356;
´
(b) C. A. Mullen and M. R. Gagne, Org. Lett., 2005, 8, 665; (c) M. Kim,
H. S. Jeong, C.-E. Yeom and B. M. Kim, Tetrahedron: Asymmetry, 2012,
23, 1019; (d) S. Doherty, J. G. Knight and H. Mehdi-Zodeh, Tetrahedron:
Asymmetry, 2012, 23, 209; (e) K. Zheng, X. Liu, S. Qin, M. Xie, L. Lin,
C. Hu and X. Feng, J. Am. Chem. Soc., 2012, 134, 17564.
15 The absolute configurations of the products were not verified, and
Scheme 2 only shows the relative configurations of them.
c
1650 Chem. Commun., 2013, 49, 1648--1650
This journal is The Royal Society of Chemistry 2013