Jian
Zhao‡
a,
Sybrand J. T.
Jonker‡
a,
Denise N.
Meyer
a,
Göran
Schulz
a,
C. Duc
Tran
a,
Lars
Eriksson
b and
Kálmán J.
Szabó
*a
aDepartment of Organic Chemistry, Stockholm University, SE-106 91 Stockholm, Sweden. E-mail: kalman.j.szabo@su.se
bDepartment of Materials and Environmental Chemistry, Stockholm University, SE-106 91 Stockholm, Sweden
First published on 19th February 2018
Tri- and tetrasubstituted allenylboronic acids were prepared via a new versatile copper-catalyzed methodology. The densely functionalized allenylboronic acids readily undergo propargylboration reactions with ketones and imines without any additives. Catalytic asymmetric propargylborylation of ketones is demonstrated with high stereoselectivity allowing for the synthesis of highly enantioenriched tertiary homopropargyl alcohols. The reaction is suitable for kinetic resolution of racemic allenylboronic acids affording alkynes with adjacent quaternary stereocenters.
Stereoselective propargylboration with allenylboron species became one of the most important transformations for creation of sterically crowded propargylic alcohols and imines.6 One of the important synthetic strategies for the formation of a tertiary stereocenter is based on the reaction of allenyl or propargylic boron reagents with ketones in the presence of a chiral catalyst (Fig. 1a). Schaus,6b Shibasaki6a and Fandrick6v reported these types of propargylboration reactions using mono- or disubstituted allenyl- and propargylboronates. Another very efficient method involves synthesis of secondary and tertiary propargylic alcohols without application of organometallic reagents using asymmetric metal catalysis (Fig. 1b).7 Krische reported an efficient method for tert-prenylation for terpenoid construction (Fig. 1c).6w By this method a propargylic all-carbon quaternary center could be created adjacent to a secondary alcohol. However, as far as we know, formation of vicinal quaternary carbon centers has never been reported for asymmetric propargylation reactions. In this paper we report our results for achievement of this goal via asymmetric propargylboration of ketones with tetrasubstituted allenylboronic acids (Fig. 1d).
However, densely functionalized, easily accessible tetrasubstituted allenyl-Bpin compounds have a relatively low reactivity profile. These compounds, such as 1a-Bpin, react directly (without additives) with aldehydes6k,9a,b but according to our studies they are completely unreactive (Fig. 2) with ketones (2a) and imines (3a) at ambient temperature. Thus, homopropargyl alcohols and amines with adjacent quaternary carbons cannot be accessed using allenyl-Bpin reagents under mild conditions, which is required for a highly selective carbon–carbon bond formation.
The structural analogy between allyl-10 and allenylboron species suggests11 that allenylboronic acids are expected to be much more reactive than allenyl-Bpin (or other diol protected boron) reagents utilized to access crowded homopropargyl alcohols and amines. However, the lack of efficient methodologies for the preparation of densely functionalized allenylboronic acids is a fundamental problem for the implementation of this concept. Therefore, we undertook development of the first transition metal catalyzed synthesis of tri- and tetra-substituted allenylboronic acids, and subsequently we have exploited the synthetically useful properties of the unprotected B(OH)2 group for synthesis of enantiomerically enriched propargylic alcohols with vicinal quaternary carbons.
Entry | Conditions | Yieldb [%] |
---|---|---|
a General procedure: 4a (0.10 mmol), 5 (0.15 mmol), mesitylcopper(I) (0.01 mmol), P(OMe)3 (0.02 mmol), ethylene glycol (0.30 mmol), and 3 Å MS were stirred in MeOH (1 mL) at −10 °C for 24 h. b 1H NMR-yields. c 10 mol%. d 20 mol%. e Protodeborylation occurs. | ||
1 | No change | 76 |
2 | CuClc and KOMed instead of MesCu | 52 |
3 | CuClc and NaOMed instead of MesCu | 49 |
4 | CuClc and LiOMed instead of MesCu | 65 |
5 | Culc and LiOMed instead of MesCu | 29 |
6 | PPh3 instead of P(OMe)3 | 46 |
7 | PCy3 or P(O-iPr)3 instead of P(OMe)3 | 0e |
8 | 1,3-Propanediol instead of ethylene glycol | 49 |
9 | Without ethylene glycol | 66 |
10 | Without 3 Å MS | 75 |
11 | At 0 °C | 16e |
12 | THF or toluene instead of MeOH | 0 |
Using the optimized conditions, allenylboronic acid 1a could be obtained with 76% NMR yield (Table 1, entry 1). When the Cu-catalyst was generated from CuCl and alkali methoxides instead of MesCu/MeOH, the yields decreased to 49–65% (entries 2–4). Using CuI instead of CuCl led to a sharp decrease in the yield to 29% (entry 5). Phosphite P(OMe)3 could be replaced by PPh3, albeit in a diminished yield of 46% (entry 6). Application of bulky phosphorus based ligands, such as PCy3 and P(O-iPr)3, led to 0% yield of 1a (entry 7). In these reactions, large amounts of protodeborylated allene formed, which indicates that 1a is probably generated but likely undergoes a Cu-catalyzed protodeborylation. In the presence of ethylene glycol (cf. entries 9 and 1), the yield increased and only traces of protodeborylation products were observed. We found that in this in situ protection step, ethylene glycol is more efficient than its homolog, 1,3-propanediol (cf. entries 1 with 8–9). The addition of molecular sieves had a relatively weak effect on the yield (entry 10). When the reaction was conducted at 0 °C instead of −10 °C a large amount of protodeborylated product formed and the yield dropped substantially. Changing the solvent from methanol to toluene or THF prevented the formation of 1a (entry 12). Allenylboronic acid 1a is oxygen sensitive and resistant to crystallization (similar to analogs 1b–j). Therefore, the purification was done by quenching the reaction mixture with 0.5 M HCl solution (to remove the glycol protecting group) and subsequent toluene extraction of the allenylboronic acid product. The resultant toluene solution of 1a (and 1b–j) can be stored under Ar (at −18 °C for several weeks) and used for all synthetic applications presented below (Tables 3–5). Compound 1a can easily be converted to allenylboronates by adding the corresponding alcohols. For example 1a and pinacol readily give 1a-Bpin (see ESI† page 6). Reaction of 1a with diethanolamine leads to 1a-ean (Fig. 3). Easy formation of 1a-ean can be exploited for further purification of 1a by implementation of a methodology reported by Santos and co-workers (Fig. 3).14
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Fig. 3 (a) and (b) Purification of allenylboronic acids 1a and 1b. (c) Attempted transformation of the pinacolate analogue 1a-Bpin with diethanolamine. |
This method is based on reaction of the (extracted) toluene solution of 1a with diethanolamine (Fig. 3a). The esterification of the B(OH)2 group was very fast12d and the diethanolamine ester of 1a (1a-ean) is precipitated from toluene. Allenylboronate 1a-ean was an air- and moisture stable solid, which could be stored for several months. We attempted purification of 1a-ean by silica gel chromatography but this purification method led to decomposition of 1a-ean. Thus, after washing of 1a-ean with ether, degassed toluene and 0.5 M HCl solution were added and the pure 1a was extracted to the toluene phase. The purification process includes a slight loss of 1a (yield 73%).
The 1H-NMR spectrum (in toluene-d8) of purified 1a (Fig. 4) clearly shows a peak (“d”) at 4.27 ppm, which belongs to the unprotected B(OH)2 group. From this spectrum it appears that the sample does not contain any glycol or other esters of the B(OH)2 group. The sample obtained by toluene extraction of the aqueous reaction mixture of the borylation is very similar (see the ESI†) to the purified one.
We have explored the synthetic scope of the above borylation reaction (Table 2) using various propargylic carbonates (4b–h, 4j) and 5a under the above (Table 1) optimized conditions. Compound 4b, a close analog of 4a reacted with excellent yield (94%) affording allenylboronic acid 1b (entry 1). The butyl substituent can be replaced with more (4c) or less (4d) sterically demanding groups to provide the corresponding products in 61–67% yield (entries 2–3). The substituent can be varied at the propargylic carbon as well. Compound 4e gives 1e with 59% yield and substrates with two different propargylic substituents (4f-g) also react readily (entries 5 and 6) providing racemic allenylboronic acids 1f-g. The borylation reaction also tolerates various types of substituents. In 4h only the propargylic carbonate is transformed, while the aliphatic carboxylate remains unchanged (entry 7). We succeeded in performing the borylation of propargyl cyclopropane 4i (entry 8). In this reaction, the cyclopropane ring opens instead of displacement of the carbonate leaving group. Even secondary propargylic carbonates (4j) could be borylated, albeit with a lower yield (34%) than their tertiary analogs (entry 9). The presented borylation method was scaled up thirty-fold with some drop of the yield to 62% (entry 1). Compound 1b could also be further purified by the Santos method (Fig. 3b), as 1b-ean precipitated as a solid. However, diethanolamine esters of the other allenylboronic acids (1c–j) were not precipitated from the toluene solution, and therefore these compounds cannot be purified further by this method.
Entry | Substrate | Product | Yieldb [%] |
---|---|---|---|
a General procedure: 4a (0.10 mmol), 5 (0.15 mmol), mesitylcopper(I) (0.01 mmol), P(OMe)3 (0.02 mmol), ethylene glycol (0.30 mmol), and 3 Å MS were stirred in MeOH (1 mL) at −10 °C for 24 h. b 1H NMR-yield. c Yield at 3 mmol scale. | |||
1 |
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94 |
62c | |||
2 |
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67 |
3 |
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61 |
4 |
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59 |
5 |
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80 |
6 |
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63 |
7 |
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83 |
8 |
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59 |
9 |
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34 |
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Fig. 5 Extension of the methodology for synthesis of allenyl boronates. a1H NMR yield. bIsolated yield. |
We tested another method based on oxidative hydrolysis of the pinacolborane functionality in the presence of NaIO4 reported by Falck and co-workers.15 This method was also used by Petasis and co-workers6u for oxidative hydrolysis of mono- and disubstituted allenyl-Bpin compounds. The oxidative hydrolysis of 1a-Bpin was successful. Using this method after the borylation procedure, we were able to obtain 1a with 63% overall yield (Fig. 5a). This yield was somewhat lower than the analog process using B2(OH)4 (5a) as the boron source (76%) but it is still viable for obtaining 1a. We note that the level of purity of 1a obtained by this multi-step procedure (Fig. 5a) is lower than by using 5a as the boronate source (Table 1, entry 1) because of the use of more chemicals (e.g. 3 equiv. NaIO4) and pinacol as the protecting group.
We have briefly studied the synthetic scope of the above described asymmetric propargylation reactions for synthesis of encumbered homopropargylic alcohols with vicinal quaternary centers including a reversed prenyl motif (Table 5). Using the above described achiral allenylboronic acids 1a–e and ketones 2c–g the expected homopropargylic alcohols formed with 90–99% ee and 62–90% yields. The studied reactions involved the parent acetophenone 2c (entry 1) and analogs with cyano 2d (entry 2), acetate 2e and bromo 2a (entry 4) functionalities (entry 3). We made several derivatives (6g–i) containing a sulfone group in order to obtain crystalline products for determination of the absolute configuration of the products (entries 5–7) via X-ray diffraction. Unfortunately, all these products (6g–i) were oils resistant to crystallization. Finally, we succeeded in obtaining crystals of the ester of 6g (ESI†), which were suitable for X-ray analysis. The absolute configuration of the stereogenic carbon in 6g-ester was R, and thus we assigned all products arising from the (S)-dibromo-BINOL 8a catalyzed reactions as the R-enantiomers. The reaction can be easily scaled up by five-fold without a significant change in yield or ee (entry 5).
Entry | Substrates | Product | Yieldb [%] | ee | |
---|---|---|---|---|---|
a EtOH (0.2 mmol) and 8a were added to 1 (0.1 mmol) in toluene (0.2 M) with 3 Å MS, then 3 h later 2 (0.15 mmol) was added and this mixture was stirred for 48 h at RT. b Isolated yields. c Reaction time 72 h. d Reaction time 90 h. Conc. was 0.1 M. 20 mol% 8a. e 0.5 mmol scale, using 30 mol% 8a and the reaction time was 90 h. | |||||
1 | 1b |
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75 | 97 |
2 | 1b |
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67 | 91 |
3 | 1b |
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90 | 96 |
4c | 1c | 2a |
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77 | 90 |
5d | 1b |
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62 (70e) | 94 (96e) |
6c | 1a | 2f |
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63 | 96 |
7c | 1e |
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64 | 99 |
Racemic allenylboronic acids are not supposed to react with high selectivity in conventional asymmetric catalysis. However, Schaus and co-workers6b have shown that disubstituted (racemic) allylboronates undergo kinetic resolution with benzophenone (2c) in the presence of 8a. We have also found that racemic 1g reacted with ketone 2a and a stoichiometric amount of 8a, affording 9 in very high enantio- (96% ee) and diastereoselectivity (Fig. 6). The reaction of 1g with 2a was slower than with the dimethyl substituted achiral allenylboronic acids most probably because the steric congestion was further increased by the presence of an isopropyl group. Therefore, the reaction temperature was increased to 45 °C, and 100 mol% of BINOL had to be employed for full conversion of ketone 2a. Interestingly, in the absence of BINOL 8a boronic acid 1g did not react with ketone 2a under the otherwise identical conditions. This is another indication that the reactivity of allenylboronic acid is increased in the presence of BINOL 8a (Fig. 6).
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Fig. 6 Kinetic resolution of 1g affording a single enantiomeric product with adjacent quaternary stereocenters. aYield is based on racemic 1g. bYield is based on the reactive enantiomer of 1g. |
As far as we know compound 9 is the first reported enantioenriched homopropargylic compound, which was synthesized by asymmetric catalysis forming adjacent quaternary stereogenic centers. Compound 9 was obtained as an oil, which resisted functionalization. The tertiary alcohol center was assigned on the basis of the X-ray structure of 6g-ester. The relative configuration was tentatively assigned as syn based on the similarities of the spectral data and optical rotation reported by Schaus for a related product.6b
The proposed catalytic cycle for the propargylboration is given in Fig. 8. Accordingly, the enantioselective version of the reaction starts with mono- or diesterification of allenyl boronic acid 1b with EtOH affording 1b-OR. This esterification process is very fast and it can be observed by 1H NMR spectroscopy (see ESI† page 27). As mentioned above,16 boronic esters of aliphatic alcohols (such as EtOH) react much slower (if at all) than allylboronic acids/boroxines with ketones.10b,11 Thus 1b-OR does not react directly with ketone 2c, effectively shutting down the racemic background reaction (Table 3, entry 3). Therefore, when the reaction was performed without EtOH (Table 4, entry 3), the yield remained high but the ee dropped considerably indicating that considerable amount of racemic product was formed by the reaction of 1b or its boroxine and 2a. Compound 1b-OR may undergo transesterification with BINOL 8a forming a highly reactive chiral allenylboronate 11a. The transesterification of aliphatic esters (such as ethyl-ester) of 1b is probably much faster than for pinacol ester. The difficult transesterification of 1a-Bpin with diethanolamine is mentioned above (Fig. 3c). The very high reactivity of BINOL esterified allylboronic acids towards electrophiles was demonstrated by our recent DFT studies.16 The high reactivity of 11a is due to the presence of phenolic oxygen atoms, which conjugate less efficiently with the empty B(pπ) orbital than the oxygen atoms of aliphatic alcohols (e.g. EtOH). Therefore, the B(pπ) orbital of 11a will be an efficient electron acceptor for the O(nπ) orbital of ketone 2c in the cyclic TS (Fig. 7) of the reaction. The stereoselectivity of the reaction is determined in the 11a + 2c → 11b process (Fig. 7). Formation of 11b involves trapping of the BINOL catalyst. The added EtOH probably mediates decomposition of 11b, effectively releasing the BINOL catalyst 8a back into the catalytic cycle. Thus, the uncatalyzed racemic propargylation can be suppressed by the “dual action” of EtOH (i.e.1b → 1b-OR and 11b → 8a processes) increasing the ee of the reaction.
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Fig. 8 Proposed mechanism for the asymmetric propargylation exemplified with the reaction of 1b with 2c. |
Footnotes |
† Electronic supplementary information (ESI) available: Detailed experimental procedures and compound characterization data are given. CCDC 1550097. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c7sc05123a |
‡ J. Z. and S. J. T. J. contributed equally. |
This journal is © The Royal Society of Chemistry 2018 |