Copper-Catalyzed Oxidative Acetalization of Boronic Esters: An Umpolung Strategy for Cyclic Acetal Synthesis

Article abstract of DOI:10.1021/acs.joc.0c00720

A protocol for the acetalization of boronic esters is described. The reaction is catalyzed by copper, and the conditions proved to be mild and were amenable to a variety of functional groups. We expanded the Chan-Lam coupling to include C(sp3) nucleophiles and converted them into corresponding acetals. This method allows for the orthogonal acetalization of substrates with reactive, acid-sensitive functional groups.

Full text of DOI:10.1021/acs.joc.0c00720

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Note
Copper-Catalyzed Oxidative Acetalization of Boronic
Esters – An Umpolung Strategy for Cyclic Acetal Synthesis
Eric Miller, and Maciej A. Walczak
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00720 • Publication Date (Web): 06 May 2020
Downloaded from pubs.acs.org on May 6, 2020
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Copper-Catalyzed Oxidative Acetalization of Boronic Esters – An Umpolung Strategy for Cyclic Acetal
Synthesis
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Eric M. Miller and Maciej A. Walczak*
Department of Chemistry, University of Colorado, Boulder, CO 80309, United States
Supporting Information Placeholder
ABSTRACT: A protocol for the acetalization of boronic esters is described. The reaction is catalyzed
by copper and the conditions proved to be mild and were amenable to a variety of functional groups.
We expand the Chan-Lam coupling to include C(sp3) nucleophiles and convert them into
corresponding acetals. This method allows for the orthogonal acetalization of substrates with
reactive, acid-sensitive functional groups.
Oxidative carbon-heteroatom bond formation reactions using transition metal-catalysis constitute one of the main
methods for the synthesis of ethers, amines, and thioethers.1-7 A number of copper mediated carbon-oxygen bond forming
reactions have significantly progressed past the classical Ullmann ether synthesis.8-14 The generality of this approach has been
demonstrated in complex systems and most reported examples focus on C(sp2) nucleophiles. Organometals such as Sn,8 Bi,9
and B10-13 are competent coupling partners with oxygen-based nucleophiles. Chan,10 Evans,11 and Lam12 simultaneously
reported the use of stoichiometric copper(II) acetate to cross-couple aryl boronic acids with phenols and aryl amines.15
Following this discovery, numerous reports detailing the use of phenols,16-26 carboxylic acids,27 sulfonamides,10,27, 28 silanols,29
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Scheme 1. Selected C-O bond forming reactions
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oximes,30 and N-hydroxyphthalimides31 in cross-couplings with aryl19-24, 26, 31-32 or vinyl18, 25, 29 partners appeared. Batey
reported aerobic oxidation using O2 as a method to employ catalytic amounts of copper with trifluoroborate salts to expand
the scope of the Chan-Evans-Lam reaction to include aliphatic alcohols.13 This report of oxidative coupling represents a
significant advance, however, still it suffered from long reaction times and included only C(sp2) boronic acid nucleophiles.
Unlike reactions with aryl boronic acids, there are far fewer examples of oxidative couplings with C(sp3) nucleophiles. Allylic
and benzylic boronic acid derivatives are the sole examples of cross-coupling reactions with phenols14 or large excess of
aliphatic alcohols.33 Despite these encouraging advances, oxidative reactions forming acetals using boronic ester or relative
derivatives have not been reported to the best of our knowledge. Unlike other methods that require Brønsted or Lewis acids
to convert the carbonyl group or a vinyl ether into an acetal (Scheme 1), an oxidative process may be prone to orthogonal
control for the acetalization process. This proposal was further supported by recent investigations from our group on
oxidative glycosylation of anomeric stannanes using iodine(III) reagents34 where unique reactivity of anomeric nucleophiles
was exploited in sequential glycosylations. These stereoconvergent reactions proceed with exclusive anomeric control and
involve a transfer of hypervalent iodine into the anomeric position. Capitalizing on these results, we wondered if α-
heteroatom substituted C(sp3) boronic esters and their derivatives could undergo similar C-O bond-forming processes,
provided that a suitable oxidant compatible with alcohol nucleophiles could be identified. Herein, we report oxidative
Scheme 2. Initial Condition Optimizations
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acetalization of a-alkoxy boronic esters catalyzed by copper and manganese salts. This method represents an orthogonal
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approach to acetal synthesis and has been demonstrated in a range of substrates.
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First, we tested which nucleophiles were suitable for the oxidative acetalization using tetrahydropyran derivatives as the
model substrates (Scheme 2). We examined reactions using copper (II) salts and iodobenzene diacetate (PIDA) as the oxidant
in the presence of excess cyclohexanol as a competent alcohol. We found that a-stannane 1 was a viable substrate for this
transformation (38%) whereas silanol 2 was resistant to the general conditions resulting in the recovery of the substrate.
Gratifyingly, boronic ester 3 and trifluoroborate 4 underwent the oxidative reaction in more satisfactory yields (48% for
both). Although these modest yields were obtained over a long reaction time (2 days), we remained optimistic for the
acetalization of a-alkoxy substrates. Boronic esters proved to be the most suitable nucleophile due to their favorable solubility
and increased reactivity relative to the other nucleophiles tested. We were pleasantly surprised that, unlike reactions of
anomeric stannanes that in the presence of copper catalyst and PIDA form anomeric esters, boronic esters form exclusively
acetals.34
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Table 1. Optimization of the Reaction Conditions
entry
1
Catalyst
oxidant
None
solvent
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
MeCN
Dioxane
CHCl2
time
2 d
5 h
5 h
5 h
5 h
5 h
5 h
5 h
5 h
5 h
5 h
5 h
5 h
yielda
0%b
Cu(OAc)2
2
Cu(OTf)2/Mn(OAc)3
Cu(OTf)2/Mn(OAc)3
Cu(OTf)2/Mn(acac)3
Cu(OTf)2/Mn(OAc)2
Cu(OTf)2/Co(OAc)2
Cu(OTf)2/Fe(acac)3
Cu(OTf)2/Mn(OAc)2
Cu(OTf)2/Mn(OAc)2
Cu(OTf)2/Mn(OAc)2
Cu(OTf)2/Mn(OAc)2
Cu(OTf)2/Mn(OAc)2
Cu(OTf)2/Mn(OAc)2
None
71%c
53%
62%
76%
73%
57%
11%
62%
0%
3
PIDA
4
PIDA
5
PIDA
6
PIDA
7
PIDA
8
PIDA
9
PhIO
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12
13
PhI(OH)OTs
PIDA
69%
58%
75%
PIDA
PIDA
Reactions performed using 0.1 mmol 3, 0.3 mmol 6, 10 mol% of each
catalyst, and 1 mL of solvent. aYield determined by NMR using 1,3,5-
trimethoxybenzene as a calibrated internal standard. bReaction performed
using 2 equivalents of Et3N as a base. cReaction performed with 2
equivalents of Mn(OAc)3·2H2O and 10 mol% Cu(OTf)2 at 80 °C.
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Encouraged by the results with boronic esters as our model substrates, we next wanted to develop useful conditions for
acetalization in a wide variety of substrates. Initially, boronic ester 3 and 3-phenyl-1-propanol 6 were chosen to optimize the
acetalization conditions (Table 1). Early attempts using stoichiometric copper (II) acetate with amine base (entry 1) yielded
no detectable amounts of the product. Through additional experimentation, we established that the yield of the acetalization
reaction could be increased if superstoichiometric amounts of manganese(III) salts (2 equiv) were added (entry 2). The
beneficial effect of Mn(III) additives in copper-catalyzed oxidations is well established.35 Based on our prior work,34 we
hypothesized hypervalent iodide oxidants could allow for the use of catalytic amounts of copper and manganese (entry 3),
however the yields suffered. Other Mn(II) and Mn(III) catalysts were tested to increase the yield (entry 4-5) and Mn(OAc)2
afforded the desired product 7 in 76% yield (entry 5). Manganese (III) salts can act as single-electron transfer (SET) oxidants
that can generate radicals,36 so we proceeded to test other SET metals even though the electron-transfer for manganese,
cobalt, and iron complexes are known to be ligand-centered processes.37 Unfortunately, both iron and cobalt provided
diminished yields (entry 6-7). With a catalytic system in hand, we attempted to compare various hypervalent iodine oxidants.
[Bis(trifluoroacetoxy)iodo]benzene (PIFA, entry 8) led to a significantly lower yield, likely due to over-oxidizing the reaction
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Scheme 3. Scope of Various Alcohols
Reactions performed using 0.2 mmol 3, 0.6 mmol 8, Cu(OTf)2 (10 mol%),
Mn(OAc)2 (10 mol%), 0.4 mmol PIDA, and 2 mL of CHCl3. aReaction
performed using 0.2 mmol 6, 0.6 mmol 2a, 2 equiv. Mn(OAc)3·2H2O and 10
mol% Cu(OTf)2 in PhMe at 80 ºC for 6 h.
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mixture. Changing the oxidant to iodosobenzene (PhIO) provided a lower yield, possibly due to the poor solubility of the
oxidant, and Koser’s reagent38 resulted in undetectable amounts of the acetal product (entry 9-10). Solvent screening revealed
that acetonitrile and 1,4-dioxane (entry 11-12) both furnished the product in acceptable, albeit lower yields. Dichloromethane
(entry 13) allowed for indistinguishable product formation, however due to the temperature of the reaction, chloroform
proved to be the solvent of choice.
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With a set of general conditions, investigation into the scope of this transformation proceeded (Scheme 3). We established
that the general conditions could be applied to acetalization reactions with benzylic alcohols to give products 9a and 9b in
81% and 80% yield, respectively. Alcohols bearing aromatic halides were tolerated to give 9b-9d in yields ranging from 80-
87%. Sterically congested alcohol such as (1R,2S,5R)-(-)-menthol was cleanly acetalized to provide 9e in 84% yield.
Conjugated alkynes endured the oxidative conditions to deliver 9f in a modest yield of 68%. As a demonstration of the
mildness of the oxidative conditions, we were able to convert an acetal derived from cyclohexanone into the corresponding
product 9g in 60% yield without the cleavage of the sensitive acetal groups. The acetalization of methyl 2,3,4-tri-O-methyl-a-
D-glucopyranoside proceeded smoothly to furnish acetalized 9h with a yield of 78%. Boc-protected amines proceeded to give
9i, 9j and 9k with no appreciable deprotection of the amine. Alcohol derivatives of therapeutics naproxen and ibuprofen were
also effective in delivering the corresponding acetal products (9l and 9m). Remarkably, electron-rich aromatic substrate 9m
was compatible with the hypervalent iodine oxidant, even though over oxidation of the aromatic ring has been shown to
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Scheme 4. Scope of Various Boron Derivatives
Reaction performed using 0.2 mmol 10, 0.6 mmol 8, Cu(OTf)2 (10 mol%),
Mn(OAc)2 (10 mol%), 0.4 mmol PIDA, and 2 mL of CHCl3.aReaction performed
using 1 mmol of 10.
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occur.39 Finally, cholesterol was acetalized to give product 9n in 60% yield. Primary and secondary alcohols were easily
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protected; however, tertiary alcohol 1-adamantol was unable to yield any product (results not shown).
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Having established conditions compatible with a variety of functional groups, we set to expand the scope of a-alkoxy
boronic esters (Scheme 4). Isochromans have been shown to produce acetals using DDQ as an oxidant in the presence of
alcohol nucleophiles.40 We found that alkyl and benzyl alcohol nucleophiles were cleanly acetalized to furnish products 11a,
11b, 11d, and 11h. It is noteworthy that unsubstituted alkynes were unreactive in producing off-target products. Propargyl
alcohol produced product 11c in 71% yield. This example provides evidence for a very fast secondary oxidation given that, if
a potential radical is formed, it is quickly oxidized to a carbocation before reacting with a radical acceptor. Boc-protected
amino alcohol gave product 11e in 75% yield. To show the scalability of the conditions, we tested this reaction on a one mmol
scale to produce 11e in comparable yields. Aromatic heterocycles gave the acetal product 11f and 11g in 66% and 93%,
respectively.
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To expand the scope of nucleophiles with the a-alkoxy boronic esters, we continued to test biomedically relevant
nucleophiles such as sulfonamides, a structural element frequently found in medicinal chemistry.41-42 Previously, the Chan-
Evans-Lam coupling was studied in the context of N-arylations43-45 and resulted in the development of a cationic Cu catalyst
operational under ambient condtions.28 Sulfonamides have been also shown to couple with cyclic ethers and isochroman
through C(sp3)-H functionalization46-47 or using metal-organic frameworks.48 These studies demonstrated that hypervalent
iodine can oxidize sulfonamides to nitrenes, leading us to replace PIDA with another oxidant.46 We tested the feasibility of
conditions already established in the optimization work (entry 2, table 2) that could be compatible with sulfonamides.
Gratifyingly, benzenesulfonamide gave the amination product 13a in 75% yield (Scheme 5). Halogenated sulfonamides
Scheme 5. Scope of Sulfonamide Substrates
Reaction performed using 0.2 mmol 3, 0.6 mmol 2a,
Mn(OAc)3·2H2O and 10 mol% Cu(OTf)2 in PhMe at 80 ºC for 6 h.
2 equiv.
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observed coupling to give 13b and 13c in 78% and 76%, respectively. Alkyl sulfonamide gave the corresponding product 13d
in 92% yield. Para-substituted electron-withdrawing groups had minimal effect on yield, as para-trifluoromethyl
benzenesulfonamide produced 13e in 73% yield. In contrast, para-methyl furnished the corresponding amidated product 13f
in a higher yield of 82% and 3-methoxy benzenesulfonamide gave 13g in 81%. To further examine the compatibility of the
oxidative conditions with diverse sulfonamides, we looked toward commercially available therapeutics. Ethoxzolamide, a
carbonic anhydrase inhibitor for the potential treatment of tuberculosis,49 yielded 13h in 55% yield. Celecoxib, a COX-
selective non-steroidal anti-inflammatory drug that relieves pain and swelling used in the treatment of rheumatoid arthritis,50
proceeded to give 13i in 76%.
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Kinetic isotope effect (KIE) and radical trapping experiments were performed to assess the mechanism of the oxidative
coupling (Supporting Information). The KIE observed is consistent with a normal secondary effect which suggests a change
in hybridization from sp3 to sp2 as the reaction proceeds and is consistent with the formation of oxocarbenium. We posited
the initial generation of a radical with manganese (III) from the boronic ester.51-54 To substantiate our hypothesis, our model
substrate 3 was reacted with both TEMPO and 1,1-diphenylethylene. However, there was no formation of any radical adducts
which could indicate the radical is oxidized faster than the formation of an adduct. Following this result, we determined the
role of copper and manganese in the reaction. Removing copper from standard conditions gave acetal 7 in just 13% yield,
highlighting the importance of copper to rapidly oxidize the radical to an oxocarbenium.49 Replacing manganese (III) with
manganese (II) produced no product confirming manganese (III) is needed to oxidize boronic esters. Combined, the KIE
studies and mechanistic studies are consistent with the generation of oxocarbenium intermediate that undergoes quenching
with a competent nucleophile.
In conclusion, we have developed copper-catalyzed oxidative acetalization of a-alkoxy boronic esters with a variety of
alcohol nucleophiles. The mild chemistry tolerates diverse functional groups including acid-sensitive protecting groups. KIE
and mechanistic testing helped elucidate the potential reaction mechanism. This protocol can allow for orthogonal
acetalization or stereospecific coupling of alcohols and C(sp3) boronic esters.
EXPERIMENTAL SECTION
General Information. All chemicals were purchased as reagent grade and used without further purification unless
otherwise noted. Solvents were filtered through a column of activated alumina prior to use. 4Å molecular sieves was
purchased from Acros Organic, Inc. Visualizations were performed with UV light and/or Hanessian’s stain. Column
1
Chromatography was performed on silica gel (230-400 mesh). H and 13C NMR spectra were recorded on Bruker/Varian
300/400/500 MHz instruments are reported as follows: chemical shift (d), multiplicity (s = singlet, d = doublet, t = triplet, q
= quartet, br = broad, m = multiplet), coupling constant (Hz), and integration. The residual solvent peaks were used from
published literature. IR measurements were performed on Agilent Cary 630 FT/IR instrument and optical rotations were
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measured on JASCO P-1030 and are reported as averages of five data points. High-resolution mass spectra (HR-MS) were
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recorded on Waters Synapt G2 HDMS q-TOF hybrid mass spectrometer. Nucleophiles 8 and 12 were commercially available
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with
few
exceptions.
3-Phenylprop-2-yn-1-ol55,
Methyl
2,3,4-tri-O-methyl-α-D-glucopyranose56,
(S)-2-(4-
5
6
isobutylphenyl)propan-1-ol57, (S)-2-(6-Methoxynaphthalen-2-yl)propan-1-ol57 4-Methylbenzenesulfonamide58, and 4-
,
7
8
Methoxybenzenesulfonamide58 were prepared according to previously reported procedures
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General Procedure for oxidative coupling reactions using PIDA. To a solution of a-alkoxy boronic ester (0.200 mmol,
1.0 equiv.) and nucleophile (0.600 mmol, 3.0 equiv.) in anh. chloroform (0.100 M), CuOTf2 (10 mol%), Mn(OAc)2 (10 mol%),
and 4Å molecular sieves were added. The mixture was allowed to stir for five minutes before (diacetoxyiodo)benzene (0.400
mmol, 2.0 equiv.) was added. The reaction mixture was heated in an oil bath (60 oC) for five hours, cooled to rt, filtered through
a pad of silica, and concentrated. The crude material was purified by column chromatography on SiO2.
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2-(3-phenylpropoxy)tetrahydro-2H-pyran (7). Colorless oil (33.5 mg, 76%), purified on silica gel (Hexanes:EtOAc,
20:1): 1H NMR (300 MHz, CDCl3) δ 7.33 – 7.25 (m, 2H), 7.24 – 7.14 (m, 3H), 4.59 (dd, J = 4.4, 2.7 Hz, 1H), 3.89 (tt, J = 8.1, 3.3
Hz, 1H), 3.79 (dt, J = 9.7, 6.6 Hz, 1H), 3.51 (dddd, J = 11.0, 5.4, 3.8, 1.3 Hz, 1H), 3.42 (dt, J = 9.7, 6.5 Hz, 1H), 2.72 (td, J = 7.5, 2.8
Hz, 2H), 2.01 – 1.67 (m, 4H), 1.67 – 1.47 (m, 4H). Characterization data matched the literature report.59
2-(Naphthalen-2-ylmethoxy)tetrahydro-2H-pyran (9a). Colorless oil (39.0 mg, 81%), purified on silica gel
1
(Hexanes:EtOAc, 20:1): IR (ATR) n = 3056, 2944, 2869, 1458, 1343, 1205, 1123, 1030, 817, 754 cm-1; H NMR (300 MHz,
CDCl3) δ 7.91 – 7.77 (m, 4H), 7.57 – 7.42 (m, 3H), 4.96 (d, J = 12.3 Hz, 1H), 4.77 (dd, J = 4.0, 3.1 Hz, 1H), 4.69 (d, J = 12.3 Hz,
1H). 4.05 – 3.90 (m, 1H), 3.65 – 3.51 (m, 1H), 1.98 – 1.51 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 135.9, 133.5, 133.1, 128.2, 128.0,
127.8, 126.7, 126.2, 126.1, 125.9, 97.9, 69.1, 62.4, 30.8, 25.7, 19.6; HRMS (ESI) m/z: [M + Na]+ calcd for C16H18O2Na 265.1204;
found 265.1235.
2-((4-Chlorobenzyl)oxy)tetrahydro-2H-pyran (9b). Colorless oil (36.0 mg, 80%), purified on silica gel (Hexanes:EtOAc,
20:1): 1H NMR (300 MHz, CDCl3) δ 7.31 (s, 4H), 4.75 (d, J = 12.2 Hz, 1H), 4.69 (dd, J = 4.0, 3.0 Hz, 1H), 4.47 (d, J = 12.2 Hz, 1H),
3.94 – 3.85 (m, 1H), 3.54 (dddd, J = 11.2, 5.0, 4.2, 1.8 Hz, 1H), 1.93 – 1.49 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 137.0, 133.4,
129.2, 128.6, 98.0, 68.2, 62.3, 30.7, 25.6, 19.5. Characterization data matched the literature report. 60
2-(3,5-Difluorophenethoxy)tetrahydro-2H-pyran (9c). Yellow oil (39.0 mg,
87%), purified on silica gel
(Hexanes:EtOAc, 20:1): IR (ATR) n = 3089, 2944, 1599, 1462, 1119, 1037, 981, 855 cm-1; 1H NMR (300 MHz, CDCl3) δ 6.82 –
6.73 (m, 2H), 6.65 (tt, J = 9.1, 2.3 Hz, 1H), 4.58 (dd, J = 4.0, 2.8 Hz, 1H), 3.94 (dt, J = 9.8, 6.8 Hz, 1H), 3.81 – 3.66 (m, 1H), 3.60
(dt, J = 9.8, 6.7 Hz, 1H), 3.54 – 3.40 (m, 1H), 2.88 (t, J = 6.6 Hz, 2H), 1.92 – 1.41 (m, 6H);13C NMR (75 MHz, CDCl3) δ 164.7 (d, J
= 12.9 Hz), 161.4 (d, J = 12.9 Hz), 143.5 (t, J = 9.2 Hz), 112.0 (d, J = 7.4 Hz), 111.8 (d, J = 7.4 Hz), 101.7 (t, J = 25.3 Hz), 98.9,
67.5, 62.4, 36.2 (t, J = 2.0 Hz), 30.7, 25.6, 19.6; 19F NMR (282 MHz, CDCl3) δ -110.92; HRMS (ESI) m/z: [M + Na]+ calcd for
C13H16F2O2Na 265.1016; found 265.1021.
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2-(3-Bromophenethoxy)tetrahydro-2H-pyran (9d). Colorless oil (49.0 mg, 86%), purified on silica gel (Hexanes:EtOAc,
20:1): 1H NMR (300 MHz, CDCl3) δ 7.42 – 7.40 (m, 1H), 7.36 – 7.31 (m, 1H), 7.19 – 7.11 (m, 2H), 4.58 (dd, J = 4.1, 2.8 Hz, 1H),
3.93 (dt, J = 9.7, 7.0 Hz, 1H), 3.77 – 3.66 (m, 1H), 3.60 (dt, J = 9.7, 6.9 Hz, 1H), 3.51 – 3.39 (m, 1H), 2.88 (t, J = 7.0 Hz, 2H), 1.89
– 1.43 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 141.8, 132.3, 130.0, 129.4, 127.8, 122.4, 98.8, 67.9, 62.3, 36.13, 30.8, 25.6, 19.6.
Characterization data matched the literature report.61
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2-(((1R,2S,5R)-2-iso-Propyl-5-methylcyclohexyl)oxy)tetrahydro-2H-pyran (9e). Colorless oil (40.0 mg, 83%),
purified on silica gel (Hexanes:EtOAc, 20:1): 1H NMR (300 MHz, CDCl3) major diastereomer δ 4.79 (t, J = 3.6 Hz, 1H), 4.03 –
3.82 (m, 1H), 3.55 – 3.42 (m, 2H), 2.35 (pd, J = 7.0, 2.6 Hz, 1H), 2.21 – 2.00 (m, 1H), 1.90 – 1.46 (m, 8H), 1.44 – 1.14 (m, 2H),
1.14 – 0.66 (m, 12H); 13C NMR (75 MHz, CDCl3) δ 101.5, 94.5, 80.1, 74.3, 63.2, 62.6, 49.1, 48.3, 43.7, 40.3, 34.7, 34.6, 32.0, 31.6,
31.5, 31.4, 25.8 (2), 25.7, 25.4, 23.4, 23.2, 22.5, 22.4, 21.4, 21.3, 20.4, 19.9, 16.4, 15.8. Characterization data matched the
literature report.62
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2-((3-Phenylprop-2-yn-1-yl)oxy)tetrahydro-2H-pyran (9f). Yellow oil (29.0 mg, 68%), purified on silica gel
(Hexanes:EtOAc, 20:1): IR (ATR) n = 3059, 2944, 2854, 1495, 1346, 1123, 1026, 907, 762, 695 cm-1; 1H NMR (300 MHz, CDCl3)
δ 7.48 – 7.42 (m, 2H), 7.34 – 7.27 (m, 3H), 4.95 – 4.83 (m, 1H), 4.53 (d, J = 15.7 Hz, 1H), 4.46 (d, J = 15.7 Hz, 1H), 3.97 – 3.82
(m, 1H), 3.67 – 3.48 (m, 1H), 1.97 – 1.49 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 132.0, 128.5, 128.4, 122.9, 97.0, 85.9, 85.3, 62.2,
54.9, 30.5, 25.5, 19.2; HRMS (ESI) m/z: [M + Na]+ calcd for C14H16O2Na 239.1048; found 239.1065.
8-((Tetrahydro-2H-pyran-2-yl)oxy)-1,4-dioxaspiro[4.5]decane (9g). Colorless oil (29.0 mg, 60%), purified on silica
gel (Hexanes:EtOAc, 20:1): IR (ATR) n = 2933, 2873, 1447, 1372, 1104, 1026, 929 cm-1; 1H NMR (300 MHz, CDCl3) δ 4.68 (dd,
J = 4.6, 2.8 Hz, 1H), 3.99 – 3.84 (m, 5H), 3.76 (td, J = 7.2, 3.5 Hz, 1H), 3.53 – 3.42 (m, 1H), 1.92 – 1.42 (m, 14H); 13C NMR (75
MHz, CDCl3) δ 108.6, 96.9, 71.7, 64.4 (2), 62.8, 31.8, 31.5, 31.4, 30.3, 28.1, 25.7, 20.0; HRMS (ESI) m/z: [M + Na]+ calcd for
C13H22O4Na 265.1416; found 265.1413.
Methyl 2,3,4-tri-O-methyl-6-O-(tetrahydro-2H-pyran-2-yl)-α-D-glucopyranose (9h). Colorless oil (50.0 mg, 78%),
purified on silica gel (Hexanes:EtOAc, 3:1): IR (ATR) n = 2936, 2840, 1447, 1164, 1104, 1030, 754 cm-1; 1H NMR (300 MHz,
CDCl3) major diastereomer δ 4.81 (d, J = 3.6 Hz, 1H), 4.64 (ddd, J = 12.7, 4.3, 3.1 Hz, 1H), 4.01 – 3.81 (m, 2H), 3.67 – 3.45 (m,
13H), 3.39 (d, J = 0.9 Hz, 3H), 3.25 – 3.05 (m, 2H), 1.99 – 1.40 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 99.5, 98.9, 97.5, 97.4, 83.9,
83.8, 82.0, 79.9, 79.6, 70.2, 70.0, 66.5, 65.9, 62.5, 62.2, 61.0 (2), 60.6, 60.5, 59.1, 55.2, 55.1, 30.7, 30.7, 25.6, 25.5, 19.7, 19.5;
HRMS (ESI) m/z: [M + Na]+ calcd for C15H28O7Na 343.1733; found 343.1725.
(2S)-tert-Butyl 2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyrrolidine-1-carboxylate (9j). Colorless oil (59.0 mg,
91%), purified on silica gel (Hexanes:EtOAc, 3:1): IR (ATR) n = 2944, 2877, 1696, 1391, 1171, 1037, 873, 776 cm-1; 1H NMR
(300 MHz, CDCl3) major diastereomer 4.81 (d, J = 3.6 Hz, 1H), 4.64 (ddd, J = 12.7, 4.3, 3.1 Hz, 1H), 4.01 – 3.81 (m, 2H), 3.67 –
3.45 (m, 13H), 3.39 (d, J = 0.9 Hz, 3H), 3.25 – 3.05 (m, 2H), 1.99 – 1.40 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 154.7, 154.6, 99.5,
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99.0, 98.3, 79.3, 68.9, 68.4, 68.0, 67.7, 62.2, 62.0, 56.9, 56.5, 46.6, 30.8 (2), 29.0, 28.7, 28.7, 28.3, 25.6 (2), 23.2, 19.5; HRMS
(ESI) m/z: [M + Na]+ calcd for C15H27NO4Na 308.1838; found 308.1848.
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(2R)-Methyl-((tert-butoxycarbonyl)amino)-3-((tetrahydro-2H-pyran-2-yl)oxy)propanoate (9k). White solid (45.0
mg, 74%), purified on silica gel (Hexanes:EtOAc, 3:1): IR (ATR) n = 3447, 2948, 2877, 1756, 1719, 1506, 1391, 1167, 1041 cm-
1; 1H NMR (300 MHz, Methanol-d4) major diastereomer δ 4.62 (dd, J = 3.8, 2.8 Hz, 1H), 4.36 (dt, J = 10.1, 4.6 Hz, 1H), 4.02 (dd,
J = 10.1, 4.9 Hz, 1H), 3.95 – 3.76 (m, 2H), 3.75 (s, 3H), 3.64 (dd, J = 10.0, 3.9 Hz, 1H), 3.57 – 3.45 (m, 1H), 1.90 – 1.48 (m, 6H),
1.45 (s, 9H); 13C NMR (75 MHz, Methanol-d4) δ 171.3, 156.5, 99.5, 98.5, 79.4, 67.3, 66.7, 62.2, 61.6, 54.2, 53.8, 51.4, 30.2, 29.9,
27.2, 25.1, 25.0, 19.1, 18.7; HRMS (ESI) m/z: [M + Na]+ calcd for C14H25NNaO6 326.1580; found 326.1567.
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2-((S)-2-(4-iso-Butylphenyl)propoxy)tetrahydro-2H-pyran (9l). Colorless oil (50.0 mg, 90%), purified on silica gel
(Hexanes:EtOAc, 20:1): IR (ATR) n = 3052, 3015, 2955, 2873, 1518, 1469, 1127, 1033, 803 cm-1; 1H NMR (300 MHz, CDCl3)
major diastereomer δ 7.15 (dd, J = 8.1, 2.2 Hz, 2H), 7.10 – 7.05 (m, 2H), 4.59 (dd, J = 3.7, 2.7 Hz, 1H), 3.88 – 3.70 (m, 1H), 3.66
– 3.55 (m, 1H), 3.55 – 3.34 (m, 2H), 3.01 (h, 1H), 2.44 (d, J = 7.1 Hz, 2H), 1.92 – 1.38 (m, 7H), 1.33 (d, J = 4.9 Hz, 6H), 0.89 (d, J
= 6.6 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 141.9, 141.8, 139.7, 139.6, 129.1 (2), 127.2 (2), 98.9, 98.6, 62.1, 62.0, 45.2, 39.8, 39.7,
30.8 (2), 30.4 (2), 25.7 (2), 22.5 (2), 19.6, 19.5, 18.5, 18.4; HRMS (ESI) m/z: [M + Na]+ calcd for C18H28O2Na 299.1987; found
299.1978.
2-((S)-2-(6-Methoxynaphthalen-2-yl)propoxy)tetrahydro-2H-pyran (9m). Colorless oil (44.0 mg, 73%), purified on
silica gel (Hexanes:EtOAc, 20:1): IR (ATR) n = 3059, 2940, 2873, 1611, 1488, 1268, 1127, 1033, 855 cm-1; 1H NMR (300 MHz,
CDCl3) major diastereomer δ 7.72 – 7.65 (m, 2H), 7.64 – 7.58 (m, 1H), 7.41 – 7.34 (m, 1H), 7.16 – 7.09 (m, 2H), 4.62 (dd, J =
4.0, 2.8 Hz, 1H), 4.02 – 3.76 (m, 1H), 3.95 (dd, J = 9.6, 6.0 Hz, 1H), 3.91 (s, 3H), 3.71 – 3.64 (m, 1H), 3.54 – 3.36 (m, 1H), 3.18
(h, J = 7.0 Hz, 1H), 1.91 – 1.43 (m, 6H), 1.40 (d, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 157.4, 139.9 (2), 133.4, 129.2 (2),
126.9 (2), 126.8, 126.7, 125.6 (2), 118.8, 118.7, 105.7, 99.0, 98.7, 62.2, 62.1, 55.4, 40.1, 30.8, 25.7, 25.6, 19.6, 19.5, 18.7, 18.6;
HRMS (ESI) m/z: [M + Na]+ calcd for C19H24O3Na 323.1623; found 323.1621.
7-Fluoro-1-(4-fluorophenethoxy)isochroman (11a). Pale yellow oil (52.0 mg, 89%), purified on silica gel
(Hexanes:EtOAc, 20:1): IR (ATR) n = 3044, 2936, 2880, 1503, 1223, 1082, 1041, 825 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.30 –
7.16 (m, 2H), 7.13 – 6.90 (m, 4H), 6.82 (dd, J = 9.0, 2.7 Hz, 1H), 5.47 (s, 1H), 4.18 – 3.94 (m, 2H), 3.91 – 3.74 (m, 2H), 3.02 –
2.83 (m, 3H), 2.58 (ddd, J = 16.4, 3.4, 1.8 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 163.1 (d, J = 32.3 Hz), 159.9 (d, J = 33.1 Hz),
135.8 (d, J = 6.8 Hz), 134.8 (d, J = 3.3 Hz), 130.5 (d, J = 7.9 Hz), 130.1 (d, J = 7.5 Hz), 129.8 (d, J = 3.0 Hz), 115.6 (d, J = 21.5 Hz),
115.2 (d, J = 21.1 Hz), 114.1 (d, J = 21.7 Hz), 96.6 (d, J = 2.1 Hz), 69.1 (d, J = 1.3 Hz), 58.2, 35.7, 27.5; 19F NMR (282 MHz, CDCl3)
δ -116.13, -117.10; HRMS (ESI) m/z: [M + Na]+ calcd for C17H16F2O2Na 313.1016; found 313.1028.
1-(Benzyloxy)isochroman (11b). Pale yellow oil (44.0 mg, 91%), purified on silica gel (Hexanes:EtOAc, 20:1): IR (ATR) n
= 3067, 3033, 2970, 2936, 2880, 1499, 1458, 1026, 1000, 750, 702 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.48 – 7.42 (m, 2H), 7.41
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– 7.27 (m, 3H), 7.26 – 7.20 (m, 3H), 7.16 – 7.10 (m, 1H), 5.63 (s, 1H), 4.90 (d, J = 12.0 Hz, 1H), 4.76 (d, J = 12.0 Hz, 1H), 4.22
(dddd, J = 12.0, 11.2, 3.4, 0.6 Hz, 1H), 3.94 (ddd, J = 11.2, 6.1, 1.6 Hz, 1H), 3.05 (dddd, J = 16.5, 12.1, 6.0, 1.0 Hz, 1H), 2.64 (dddd,
J = 16.5, 3.4, 1.6, 0.7 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 138.3, 134.3, 134.2, 128.6, 128.3 (2), 127.8, 127.7, 126.4, 95.8, 69.5,
58.1, 28.2; HRMS (ESI) m/z: [M + Na]+ calcd for C16H16O2Na 263.1048; found 263.1062.
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1-(Prop-2-yn-1-yloxy)isochroman (11c). Pale yellow oil (27.0 mg, 71%), purified on silica gel (Hexanes:EtOAc, 20:1): IR
(ATR) n = 3294, 3070, 3033, 2925, 1391, 1097, 1074, 1030, 754 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.31 – 7.20 (m, 3H), 7.17 –
7.09 (m, 1H), 5.78 (s, 1H), 4.46 (dd, J = 15.8, 2.4 Hz, 1H), 4.37 (dd, J = 15.8, 2.4 Hz, 1H), 4.13 (dddd, J = 12.1, 11.2, 3.3, 0.7 Hz,
1H), 3.93 (ddd, J = 11.2, 6.1, 1.5 Hz, 1H), 3.05 (dddd, J = 16.5, 12.1, 6.0, 1.0 Hz, 1H), 2.64 (dddd, J = 16.5, 3.4, 1.6, 0.7 Hz, 1H),
2.49 (t, J = 2.4 Hz, 1H; 13C NMR (75 MHz, CDCl3) δ 134.3, 133.6, 128.5, 128.4, 127.8, 126.5, 95.0, 79.9, 74.6, 58.3, 54.5, 28.1;
HRMS (ESI) m/z: [M + Na]+ calcd for C12H12O2Na 211.0735; found 211.0726.
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1-(4-Fluorophenethoxy)isochroman (11d). White solid (35.0 mg, 64%), purified on silica gel (Hexanes:EtOAc, 20:1): IR
(ATR) n = 3070, 3033, 2936, 2880, 1514, 1223, 1078, 1033, 829, 750 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.31 – 7.21 (m, 4H),
7.19 – 7.11 (m, 2H), 7.08 – 6.96 (m, 2H), 5.56 (s, 1H), 4.18 – 4.02 (m, 2H), 3.96 – 3.81 (m, 2H), 3.15 – 2.90 (m, 3H), 2.64 (ddd,
J = 16.5, 3.6, 1.7 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 163.3, 160.1, 134.9 (d, J = 3.1 Hz), 134.2, 130.5 (d, J = 7.9 Hz), 128.4 (d, J
= 25.2 Hz), 127.6, 126.4, 115.2 (d, J = 21.1 Hz), 97.1, 69.0, 68.9, 58.1, 35.7, 28.1; 19F NMR (282 MHz, CDCl3) δ -117.24; HRMS
(ESI) m/z: [M + Na]+ calcd for C17H17FO2Na 295.1110; found 295.1115.
tert-Butyl (3-((7-methylisochroman-1-yl)oxy)propyl)carbamate (11e). Colorless oil (48.0 mg, 75%), purified on silica
gel (Hexanes:EtOAc, 4:1): IR (ATR) n = 3361, 2974, 2933, 2880, 1700, 1510, 1369, 1164, 1048, 1019, 817 cm-1; 1H NMR (300
MHz, CDCl3) δ 7.10 – 6.96 (m, 3H), 5.50 (s, 1H), 4.78 (s, 1H), 4.09 (td, J = 11.5, 3.4 Hz, 1H), 3.99 – 3.82 (m, 2H), 3.68 (dt, J = 9.9,
6.0 Hz, 1H), 3.28 (ddq, J = 19.2, 12.6, 6.3 Hz, 2H), 2.97 (ddd, J = 17.3, 11.8, 5.9 Hz, 1H), 2.58 (ddd, J = 16.5, 3.4, 1.6 Hz, 1H), 2.32
(s, 3H), 1.85 (p, J = 6.4 Hz, 2H), 1.43 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 136.1, 133.9, 131.1, 129.2, 128.5, 127.9, 97.1, 66.1,
58.3, 38.6, 30.0, 28.6, 28.5, 27.8, 21.2; HRMS (ESI) m/z: [M + Na]+ calcd for C18H27NO4Na 344.1838; found 344.1865.
Procedure for 1 mmol oxidative acetalization. 4,4,5,5-tetramethyl-2-(7-methylisochroman-1-yl)-1,3,2-dioxaborolane
(272 mg, 1.00 mmol), 3-(Boc-amino)-1-propanol (525 mg, 3.00 mmol), Cu(OTf)2 (36.1 mg, 0.100 mmol), Mn(OAc)2 (17.3 mg,
0.100 mmol), and 4Å molecular sieves were added in chloroform (10.00 mL). The mixture was allowed to stir for five minutes
before (diacetoxyiodo)benzene (644 mg, 2.00 mmol) was added. The reaction mixture was heated at 60 ºC for 5 h, cooled to
rt, filtered through a pad of silica, and concentrated. The crude mixture was purified via flash chromatography on SiO2
(Hexanes:EtOAc, 4:1) to afford 11e (255 mg, 79%) as a colorless oil.
1-(Furan-2-ylmethoxy)-7-methylisochroman (11f). Yellow oil (32.0 mg, 66%), purified on silica gel (Hexanes:EtOAc,
20:1):1H NMR (300 MHz, CDCl3) δ 7.46 (dd, J = 1.9, 0.9 Hz, 1H), 7.11 – 6.93 (m, 3H), 6.49 – 6.28 (m, 2H), 5.60 (s, 1H), 4.79 (d, J
= 12.9 Hz, 1H), 4.72 (d, J = 12.9 Hz, 1H), 4.17 (dddd, J = 12.0, 11.2, 3.4, 0.7 Hz, 1H), 3.93 (ddd, J = 11.2, 6.0, 1.5 Hz, 1H), 3.00
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(ddd, J = 17.5, 12.1, 6.0 Hz, 1H), 2.58 (ddd, J = 16.5, 3.5, 1.4 Hz, 1H), 2.30 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 151.8, 143.0,
136.0, 133.7, 131.1, 129.2, 128.4, 128.0, 110.4, 109.7, 95.6, 61.2, 58.3, 27.8, 21.2; HRMS (ESI) m/z: [M + Na]+ calcd for
C15H16O3Na 267.0997; found 267.1025.
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4-(((7-Methylisochroman-1-yl)oxy)methyl)-2-phenyloxazole (11g). Colorless oil (60.0 mg, 93%), purified on silica gel
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CDCl3) δ 8.13 – 7.98 (m, 2H), 7.75 – 7.67 (m, 1H), 7.49 – 7.42 (m, 3H), 7.15 – 6.93 (m, 4H), 5.71 (s, 1H), 4.88 (dd, J = 12.7, 1.0
Hz, 1H), 4.76 (dd, J = 12.7, 1.0 Hz, 1H), 4.20 (dddd, J = 12.0, 11.2, 3.4, 0.6 Hz, 1H), 3.95 (ddd, J = 11.1, 6.0, 1.6 Hz, 1H), 3.01 (ddd,
J = 17.5, 12.1, 6.0 Hz, 1H), 2.60 (ddd, J = 16.5, 3.6, 1.5 Hz, 1H), 2.31 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.1, 139.5, 136.5,
136.0, 133.7, 131.2, 130.5, 129.3, 128.9, 128.4, 128.2, 127.7, 126.6, 96.4, 61.6, 58.4, 27.8, 21.2; HRMS (ESI) m/z: [M + Na]+
calcd for C20H19NO3Na 344.1263; found 344.1258.
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1-(4-Fluorophenethoxy)-7-methylisochroman (11h). Pale yellow oil (45.0 mg, 79%), purified on silica gel
(Hexanes:EtOAc, 20:1):IR (ATR) n = 3018, 2925, 2880, 1514, 1223, 1078, 1041, 817 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.28 –
7.20 (m, 2H), 7.09 – 6.95 (m, 4H), 6.94 – 6.89 (m, 1H), 5.49 (s, 1H), 4.15 – 3.96 (m, 2H), 3.93 – 3.77 (m, 2H), 3.06 – 2.84 (m,
3H), 2.56 (ddd, J = 16.5, 3.6, 1.7 Hz, 1H), 2.31 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 163.3, 160.1, 136.0, 134.9 (d, J = 3.2 Hz),
133.9, 131.1, 130.5 (d, J = 7.8 Hz), 129.2, 128.2 (d, J = 34.4 Hz), 115.2 (d, J = 21.2 Hz),, 97.2, 69.0 (2), 58.2, 35.7, 27.8, 21.2; 19
F
NMR (282 MHz, CDCl3) δ -117.29; HRMS (ESI) m/z: [M + Na]+ calcd for C18H19FO2Na 309.1267; found 309.1291.
General Procedure for oxidative coupling reactions using Mn(OAc)3·2H2O.
To a solution of a-alkoxy boronic ester (1.0 equiv.) and nucleophile (3.0 equiv.) in anh. toluene (0.100 M), CuOTf2 (10
mol%), Mn(OAc)3·H2O (2.0 equiv.), and 4Å molecular sieves were added. The reaction mixture was heated in an oil bath (80
oC) for six hours, cooled to rt, filtered through a pad of silica, and concentrated. The crude material was purified by column
chromatography on SiO2.
tert-Butyl ((2S)-1-(1H-indol-3-yl)-3-((tetrahydro-2H-pyran-2-yl)oxy)propan-2-yl)carbamate (9i). Yellow solid
(26.0 mg, 69%) was obtained from 0.100 mmol of a-alkoxy boronic ester and purified on silica gel (Hexanes:EtOAc, 50:1): IR
(ATR) n = 3413, 3335, 3011, 2933, 2873, 1693, 1503, 1167, 1033, 743 cm-1; 1H NMR (300 MHz, CDCl3) major diastereomer δ
8.14 (s, 1H), 7.70 (t, J = 7.0 Hz, 1H), 7.35 (s, 1H), 7.23 – 7.07 (m, 2H), 7.03 (t, J = 2.9 Hz, 1H), 5.08 (s, 1H), 4.59 (t, J = 3.5 Hz, 1H),
4.21 – 3.96 (m, 1H), 3.93 – 3.78 (m, 1H), 3.71 (td, J = 9.9, 9.5, 4.3 Hz, 1H), 3.56 – 3.33 (m, 2H), 3.04 (dd, J = 7.7, 3.7 Hz, 2H), 1.94
– 1.50 (m, 6H), 1.44 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 155.7, 136.3, 128.1, 122.8, 122.1, 119.5, 119.2, 112.6, 112.4, 111.1,
99.9, 99.0, 79.3, 77.4, 68.5, 68.4, 63.0, 62.2, 51.3, 50.7, 30.9, 30.7, 29.8, 28.6, 27.7, 27.3, 25.6, 25.5, 20.0, 19.5; HRMS (ESI) m/z:
[M + Na]+ calcd for C21H30N2O4Na 397.2103; found 397.2130.
2-(((3S,8S,9S,10R,13R,14S,17R)-10,13-Dimethyl-17-((R)-6-methylheptan-2-yl)-
2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)tetrahydro-2H-pyran
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(9n). White solid (28.0 mg, 60%), purified on silica gel (Hexanes:EtOAc, 50:1): 1H NMR (300 MHz, CDCl3) major diastereomer
δ 5.46 – 5.23 (m, 1H), 4.71 (dd, J = 4.8, 2.8 Hz, 1H), 4.03 – 3.77 (m, 1H), 3.68 – 3.28 (m, 2H), 2.42 – 2.13 (m, 2H), 2.09 – 0.75
(m, 44H), 0.67 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 141.2, 141.1, 121.7 (2), 97.1, 97.0, 76.2 (2), 63.1, 63.0, 56.9, 56.3, 50.4, 50.3,
42.5, 40.4, 39.9, 39.7, 38.9, 37.6, 37.4, 37.0, 36.9, 36.3, 35.9, 32.1 (2), 31.5, 31.4, 29.9, 28.4, 28.2, 28.1, 25.7, 24.5, 24.0, 23.0,
22.7, 21.2, 20.3, 20.2, 19.5, 18.9, 12.0. Characterization data matched the literature report. 60
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N-(tetrahydro-2H-pyran-2-yl)benzenesulfonamide (13a). White solid (36.0 mg, 75%), purified on silica gel
(Hexanes:EtOAc, 3:1): IR (ATR) n = 3279, 3067, 2948, 2858, 1451, 1328, 1171, 1082, 728 cm-1; 1H NMR (300 MHz, CDCl3) δ
7.99 – 7.84 (m, 2H), 7.62 – 7.40 (m, 3H), 5.41 (d, J = 9.5 Hz, 1H), 4.77 (td, J = 9.3, 2.5 Hz, 1H), 3.69 (dtd, J = 11.7, 3.7, 1.6 Hz, 1H),
3.45 – 3.28 (m, 1H), 1.81 (dddd, J = 11.2, 7.9, 4.3, 1.7 Hz, 2H), 1.68 – 1.31 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 141.8, 132.6,
128.9, 127.2, 82.1, 66.3, 31.9, 24.8, 22.5; HRMS (ESI) m/z: [M + Na]+ calcd for C11H15NO3SNa 264.0670; found 264.0703.
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4-Chloro-N-(tetrahydro-2H-pyran-2-yl)benzenesulfonamide (13b). White solid (43.0 mg, 78%), purified on silica gel
(Hexanes:EtOAc, 3:1): IR (ATR) n = 3256, 3071, 2942, 2842, 1455, 1301, 1165, 1079, 728 cm-1; 1H NMR (300 MHz, CDCl3) δ
7.92 – 7.79 (m, 2H), 7.49 – 7.38 (m, 2H), 5.40 (d, J = 9.5 Hz, 1H), 4.76 (td, J = 9.4, 2.4 Hz, 1H), 3.70 (dtd, J = 11.8, 3.9, 1.6 Hz, 1H),
3.50 – 3.26 (m, 1H), 1.90 – 1.76 (m, 2H), 1.65 – 1.30 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 140.4, 139.1, 129.1, 128.8, 82.2, 66.4,
31.9, 24.7, 22.5; HRMS (ESI) m/z: [M + Na]+ calcd for C11H14ClNO3SNa 298.0281; found 298.0301.
3,4-Difluoro-N-(tetrahydro-2H-pyran-2-yl)benzenesulfonamide (13c). Colorless oil (42.0 mg, 76%), purified on silica
gel (Hexanes:EtOAc, 3:1): IR (ATR) n = 3283, 3126, 3063, 2948, 2858, 1514, 1283, 1149, 683 cm-1; 1H NMR (300 MHz, CDCl3)
δ 7.88 – 7.62 (m, 2H), 7.37 – 7.18 (m, 1H), 5.38 (d, J = 9.6 Hz, 1H), 4.77 (td, J = 9.5, 2.4 Hz, 1H), 3.83 – 3.62 (m, 1H), 3.50 – 3.31
(m, 1H), 1.92 – 1.78 (m, 2H), 1.70 – 1.29 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 154.8 (d, J = 12.5 Hz), 151.5, 151.3, 148.3 (d, J =
13.4 Hz), 138.7 (dd, J = 4.8, 4.1 Hz), 124.5, 124.4 (dd, J = 7.4, 4.0 Hz), 118.0, 117.7, 117.4 (dd, J = 20.1, 1.7 Hz), 82.3, 66.5, 31.9,
24.7, 22.6; 19F NMR (282 MHz, CDCl3) δ -130.05, -134.34; HRMS (ESI) m/z: [M + Na]+ calcd for C11H13F2NO3SNa 300.0482;
found 300.0515.
1-Phenyl-N-(tetrahydro-2H-pyran-2-yl)methanesulfonamide (13d). Colorless oil (47.0 mg, 92%), purified on silica gel
(Hexanes:EtOAc, 3:1): IR (ATR) n = 3257, 3067, 3037, 2948, 2858, 2363, 1458, 1328, 1082, 1041, 702 cm-1; 1H NMR (300 MHz,
CDCl3) δ 7.52 – 7.45 (m, 2H), 7.42 – 7.34 (m, 3H), 4.92 (d, J = 9.9 Hz, 1H), 4.68 (td, J = 10.0, 2.2 Hz, 1H), 4.41 (d, J = 13.6 Hz, 1H),
4.35 (d, J = 13.6 Hz, 1H), 4.10 – 3.96 (m, 1H), 3.64 – 3.49 (m, 1H), 1.95 – 1.77 (m, 2H), 1.67 – 1.49 (m, 3H), 1.41 – 1.27 (m, 1H);
13C NMR (75 MHz, CDCl3) δ 131.3, 129.5, 128.8, 128.7, 82.7, 67.2, 61.1, 31.8, 25.0, 23.0; HRMS (ESI) m/z: [M + Na]+ calcd for
C12H17NO3SNa 278.0827; found 278.0862.
N-(Tetrahydro-2H-pyran-2-yl)-4-(trifluoromethyl)benzenesulfonamide (13e). Colorless oil (45.0 mg, 73%), purified
on silica gel (Hexanes:EtOAc, 3:1): IR (ATR) n = 3283, 3054, 2929, 2880, 1559, 1454, 1328, 1171, 1067, 1041, 717 cm-1; 1H
NMR (300 MHz, CDCl3) δ 8.13 – 7.99 (m, 2H), 7.82 – 7.66 (m, 2H), 5.41 (d, J = 9.5 Hz, 1H), 4.79 (td, J = 9.5, 2.4 Hz, 1H), 3.69
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(dtd, J = 11.7, 3.8, 1.8 Hz, 1H), 3.49 – 3.27 (m, 1H), 1.95 – 1.75 (m, 2H), 1.71 – 1.29 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 145.5,
134.5, 134.1, 127.8, 126.0 (q, J = 3.8 Hz),125.22, 82.3, 66.6, 31.9, 24.7, 22.6; 19F NMR (282 MHz, CDCl3) δ -63.11; HRMS (ESI)
m/z: [M + Na]+ calcd for C12H14F3NO3SNa 332.0544; found 332.0578.
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4-Methyl-N-(tetrahydro-2H-pyran-2-yl)benzenesulfonamide (13f). Colorless oil (21.0 mg, 82%) was obtained from
0.100 mmol of a-alkoxy boronic ester and purified on silica gel (Hexanes:EtOAc, 3:1): IR (ATR) n = 3282, 3054, 2948, 2858,
1415, 1326, 1171, 1072, 728 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.00 – 7.66 (m, 2H), 7.40 – 7.00 (m, 2H), 5.26 (d, J = 9.6 Hz, 1H),
4.75 (td, J = 9.4, 2.4 Hz, 1H), 3.71 (dtd, J = 11.8, 3.8, 1.7 Hz, 1H), 3.47 – 3.31 (m, 1H), 2.41 (s, 3H), 1.93 – 1.74 (m, 2H), 1.70 –
1.31 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 143.4, 138.9, 129.5, 127.3, 82.2, 66.4, 32.0, 24.8, 22.6, 21.7; HRMS (ESI) m/z: [M +
Na]+ calcd for C12H17NO3SNa 278.0827; found 278.0854.
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3-Methoxy-N-(tetrahydro-2H-pyran-2-yl)benzenesulfonamide (13g). Colorless oil (42.0 mg, 81%), purified on silica
gel (Hexanes:EtOAc, 3:1): IR (ATR) n = 3275, 3054, 2944, 2854, 1599, 1436, 1320, 1246, 1149, 1037, 698 cm-1; 1H NMR (300
MHz, CDCl3) δ 7.50 (ddd, J = 7.7, 1.7, 1.0 Hz, 1H), 7.45 (dd, J = 2.6, 1.6 Hz, 1H), 7.37 (ddd, J = 8.1, 7.7, 0.4 Hz, 1H), 7.07 (ddd, J =
8.3, 2.6, 1.0 Hz, 1H), 5.31 (d, J = 9.5 Hz, 1H), 4.77 (td, J = 9.3, 2.4 Hz, 1H), 3.84 (s, 3H), 3.73 (dtd, J = 11.7, 3.8, 1.7 Hz, 1H), 3.48
– 3.33 (m, 1H), 1.82 (dddd, J = 11.1, 7.8, 4.1, 1.6 Hz, 2H), 1.67 – 1.49 (m, 2H), 1.48 – 1.33 (m, 4H); 13C NMR (75 MHz, CDCl3) δ
159.8, 143.0, 129.9, 119.4, 119.3, 111.8, 82.2, 66.4, 55.7, 32.0, 24.8, 22.5; HRMS (ESI) m/z: [M + Na]+ calcd for C12H17NO4SNa
294.0776; found 294.0775.
6-Ethoxy-N-(tetrahydro-2H-pyran-2-yl)benzo[d]thiazole-2-sulfonamide (13h). Colorless oil (19.0 mg, 55%) was
obtained from 0.100 mmol of a-alkoxy boronic ester and 0.200 mmol of sulfonamide. Purified on silica gel (Hexanes:EtOAc,
3:1): IR (ATR) n = 3275, 3057, 2934, 2852, 1599, 1430, 1242, 1149, 1037, 698 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.04 (d, J =
9.0 Hz, 1H), 7.33 (d, J = 2.5 Hz, 1H), 7.17 (dd, J = 9.1, 2.5 Hz, 1H), 5.85 (d, J = 9.7 Hz, 1H), 4.86 (td, J = 9.3, 2.6 Hz, 1H), 4.12 (q, J
= 7.0 Hz, 2H), 3.72 – 3.61 (m, 1H), 3.50 – 3.27 (m, 1H), 1.96 – 1.75 (m, 2H), 1.65 – 1.36 (m, 4H), 1.47 (t, J = 7.0 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 159.0, 146.8, 138.6, 126.0, 118.1, 104.2, 82.5, 66.5, 64.4, 31.6, 29.9, 24.6, 22.3, 14.9; HRMS (ESI) m/z: [M +
Na]+ calcd for C14H18N2O4S2Na 365.0606; found 365.0641.
N-(Tetrahydro-2H-pyran-2-yl)-4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide
(13i).
Colorless oil (23.0 mg, 75%) was obtained from 0.066 mmol of a-alkoxy boronic ester and 0.131 mmol of sulfonamide.
Purified on silica gel (Hexanes:EtOAc, 3:1): IR (ATR) n = 3283, 3022, 2929, 2858, 1603, 1477, 1238, 1164, 750 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.98 – 7.84 (m, 2H), 7.50 – 7.36 (m, 2H), 7.22 – 7.04 (m, 4H), 6.73 (d, J = 0.6 Hz, 1H), 5.16 (d, J = 9.6 Hz,
1H), 4.75 (td, J = 9.4, 2.5 Hz, 1H), 3.73 – 3.59 (m, 1H), 3.41 – 3.18 (m, 1H), 2.37 (s, 3H), 1.90 – 1.75 (m, 2H), 1.64 – 1.29 (m, 4H);
13C NMR (75 MHz, CDCl3) δ 145.3, 143.9, 142.5, 141.4, 139.8, 129.8, 128.9, 128.4, 125.9, 125.3, 106.4, 82.2, 66.5, 32.0, 29.9,
24.8, 22.5, 21.5; 19F NMR (282 MHz, CDCl3) δ -62.43; HRMS (ESI) m/z: [M + Na]+ calcd for C22H22F3N3O3SNa 488.1232; found
488.1263.
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Procedure for borylation of 3,4-dihydropyran. 4,4,5,5-Tetramethyl-2-(tetrahydro-2H-pyran-2-yl)-1,3,2-dioxaborolane
(3). A flame-dried round-bottom flask was charged with 3,4-dihydropyran (1.30 mL, 15.0 mmol, 1.00 equiv), purged 3x with
N2, and dissolved in dry THF (15 mL). The reaction was cooled to -78 °C and tert-butyllithium (8.80 mL, 1.70 M, 15.0 mmol,
1.00 equiv) was added dropwise and stirred for 30 min at 0 °C. Trimethyl borate (1.84 mL, 16.5 mmol, 1.10 equiv) was added
and the ice bath was removed and the reaction was stirred for 1 h at ambient temperature. Pinacol (2.20 g, 18.8 mmol, 1.25
equiv) dissolved in anh. THF (15.0 mL) was added and the reaction was allowed to stir for another hour. Acetic acid (1.70 mL,
30.0 mmol, 2.00 equiv) was added and the reaction stirred for 12 h. The mixture was quenched with H2O and the aqueous
layer was washed twice with EtOAc, the organic layers were collected, dried with Na2SO4, filtered, and concentrated. The
crude material was charged with Pd/C (200 mg, 10 w/w%) and back-filled with H2. To the crude mixture was added a 1:1
EtOAc/MeOH (75.0 mL) solution and the reaction was allowed to stir for 12 h. After completion it was filtered through celite
and concentrated. The crude material was purified via flash chromatography on SiO2 (Hexanes:Et2O, 10:1) to afford 3 (1.20 g,
38%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 4.11 – 3.88 (m, 1H), 3.57 – 3.08 (m, 2H), 1.91 – 1.74 (m, 1H), 1.74 – 1.37
(m, 4H), 1.27 (s, 12H). Characterization data matched the literature report.63
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General Procedure for borylation of isochromans
A flame-dried round-bottom flask was charged with isochroman (1.00 equiv), purged 3x with N2, and dissolved in dry THF
(0.50 M). The reaction was cooled to -78 °C and TMEDA (1.20 equiv) was added followed by tert-butyllithium (1.10 equiv)
dropwise and stirred for 30 min at -78 °C. Trimethyl borate (1.20 equiv) was added and the reaction was stirred for 1 h
warming up to ambient temperature. Pinacol (1.20 equiv) dissolved in anh. THF (1.00 M) was added and the reaction was
allowed to stir for another hour. Acetic acid (2.00 equiv) was added and the reaction stirred for 12 h. The mixture was
quenched with H2O and the aqueous layer was washed twice with EtOAc, the organic layers were collected, dried with Na2SO4,
filtered, and concentrated. The crude material was purified via flash chromatography on deactivated SiO2.
2-(7-Fluoroisochroman-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. Pale yellow oil (205.0 mg, 74%), purified on
silica gel (Hexanes:EtOAc, 4:1): IR (ATR) n = 3074, 2981, 2933, 2858, 1734, 1499, 1376, 1275, 1242, 1093 cm-1; 1H NMR (300
MHz, CDCl3) δ 7.11 – 6.97 (m, 2H), 6.81 (tdd, J = 8.5, 2.7, 1.0 Hz, 1H), 4.69 (s, 1H), 4.25 (ddd, J = 11.1, 5.8, 2.4 Hz, 1H), 3.66 (td,
J = 11.0, 3.5 Hz, 1H), 3.14 – 2.94 (m, 1H), 2.60 (dt, J = 16.0, 3.1 Hz, 1H), 1.29 (d, J = 3.9 Hz, 12H); 13C NMR (75 MHz, CDCl3) δ
162.7, 159.5, 137.5, 137.4, 130.6, 130.5, 128.5, 128.4, 112.9, 112.6, 111.4, 111.1, 84.6, 65.9, 28.2, 25.0, 24.7; HRMS (ESI) m/z:
[M + Na]+ calcd for C15H20BFO3Na 301.1387; found 301.1390.
2-(Isochroman-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. Colorless oil (1.34 g, 74%), purified on silica gel
(Hexanes:EtOAc, 4:1): IR (ATR) n = 3067, 2981, 2923, 1730, 1376, 1343, 1145, 1097 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.35 –
7.22 (m, 1H), 7.20 – 7.04 (m, 3H), 4.75 (t, J = 1.5 Hz, 1H), 4.27 (ddd, J = 11.0, 5.8, 2.4 Hz, 1H), 3.71 (td, J = 11.0, 3.4 Hz, 1H), 3.24
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– 2.97 (m, 1H), 2.73 – 2.54 (m, 1H), 1.29 (d, J = 4.8 Hz, 12H); 13C NMR (75 MHz, CDCl3) δ 135.7, 133.0, 129.3, 125.9, 125.7,
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4,4,5,5-Tetramethyl-2-(7-methylisochroman-1-yl)-1,3,2-dioxaborolane. Colorless oil (1.02 g, 91%), purified on silica
gel (Hexanes:EtOAc, 4:1):IR (ATR) n = 3065, 2981, 2925, 2858, 1730, 1376, 1343, 1145, 1097 cm-1; 1H NMR (300 MHz, CDCl3)
δ 7.10 (d, J = 1.8 Hz, 1H), 7.04 – 6.80 (m, 2H), 4.71 (s, 1H), 4.25 (ddd, J = 11.0, 5.8, 2.3 Hz, 1H), 3.67 (td, J = 11.0, 3.4 Hz, 1H),
3.07 (ddd, J = 16.5, 10.8, 5.9 Hz, 1H), 2.59 (d, J = 16.1 Hz, 1H), 2.29 (s, 3H), 1.30 (d, J = 3.7 Hz, 12H); 13C NMR (75 MHz, CDCl3)
δ 135.3 (2), 129.8, 129.1, 126.4, 124.9, 84.3, 65.9, 28.4, 25.0, 24.5, 21.3; HRMS (ESI) m/z: [M + Na]+ calcd for C16H23BO3Na
297.1638; found 297.1639.
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Deuterium Kinetic Isotope Effect
Synthesis of 4,4,5,5-Tetramethyl-2-(tetrahydro-2D-pyran-2-yl)-1,3,2-dioxaborolane (14). A flame-dried round-
bottom flask was charged with 3,4-dihydropyran (1.30 mL, 15.0 mmol, 1.00 equiv), purged 3x with N2, and dissolved in dry
THF (15 mL). The reaction was cooled to -78 °C and tert-butyllithium (8.80 mL, 1.70 M, 15.0 mmol, 1.00 equiv) was added
dropwise and stirred for 30 min at 0 °C. Trimethyl borate (1.84 mL, 16.5 mmol, 1.10 equiv) was added and the ice bath was
removed and the reaction was stirred for 1 h at ambient temperature. Pinacol (2.20 g, 18.8 mmol, 1.25 equiv) dissolved in
anh. THF (15.0 mL) was added and the reaction was allowed to stir for another hour. Acetic acid (1.70 mL, 30.0 mmol, 2.00
equiv) was added and the reaction stirred for 12 h. The mixture was quenched with H2O and the aqueous layer was washed
twice with EtOAc, the organic layers were collected, dried with Na2SO4, filtered, and concentrated. A portion (250 mg, 1.19
mmol, 1.00 equiv.) of the crude material was charged with Pd/C (25 mg, 10 w/w%) and back-filled with D2. To the crude
mixture was added a 1:1 Acetone-d6/D2O (5.00 mL) solution and the reaction was allowed to stir for 12 h. After completion it
was filtered through celite and concentrated. The crude material was purified via flash chromatography on SiO2
(Hexanes:Et2O, 10:1) to afford 14 (95.0 mg, 38%) as a colorless oil: IR (ATR) n = 2981, 2923, 1720, 1379, 1343, 1141, 1097
cm-1; 1H NMR (300 MHz, CDCl3) δ 4.07 – 3.97 (m, 1H), 3.46 – 3.35 (m, 1H), 1.90 – 1.79 (m, 1H), 1.75 – 1.41 (m, 2H), 1.29 (d, J =
1.4 Hz, 12H); 13C NMR (75 MHz, CDCl3) δ 84.0, 77.4, 69.8, 26.4, 26.3, 24.9 (2); HRMS (ESI) m/z: [M + Na]+ calcd for
C11H19D2BO3Na 237.1607; found 237.1618.
DKIE experiment. 4,4,5,5-Tetramethyl-2-(tetrahydro-2H-pyran-2-yl)-1,3,2-dioxaborolane 3 (14.1 mg, 0.066 mmol),
4,4,5,5-Tetramethyl-2-(tetrahydro-2D-pyran-2-yl)-1,3,2-dioxaborolane 14 (14.0 mg, 0.066 mmol), 3-phenyl-1-propanol 6
(27.0 mg, 0.198 mmol), Cu(OTf)2 (2.5 mg, 0.007 mmol), Mn(OAc)2 (1.2 mg, 0.007 mmol), and 4Å molecular sieves were added
in chloroform (700 µL). The mixture was allowed to stir for five minutes before (diacetoxyiodo)benzene (42.5 mg, 0.132
mmol) was added. The reaction mixture was heated at 60 ºC for 30 min, cooled to rt, filtered through a pad of silica, and
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concentrated. The KIE value represents the average of four separate runs. Based on the H NMR result a KIE of 1.50 was
determined.
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Detailed experimental procedures, copies of NMR spectra for all new compounds. The Supporting
Information is available free of charge on the ACS Publications website.
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AUTHOR INFORMATION
Corresponding Author
maciej.walczak@colorado.edu
Author Contributions
The manuscript was written through contributions of all authors.
ACKNOWLEDGMENT
This work was supported by the University of Colorado Boulder and National Science Foundation
(CAREER Award No. CHE-1753225).
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