Metal- and O2-Free Oxidative C-C Bond Cleavage of Aromatic Aldehydes

Article abstract of DOI:10.1021/acs.joc.7b00784

An oxidative C-C cleavage of aldehydes requiring neither metals nor O₂ was discovered. Homobenzylic aldehydes and α-substituted homobenzylic aldehydes were cleaved to benzylic aldehydes and ketones, respectively, using nitrosobenzene as an oxidant. This reaction is chemoselective for aromatic aldehydes, as an aliphatic aldehyde was unreactive under these conditions, and other reactive functionality such as ketones and free alcohols are tolerated. A mechanism accounting for the fate of the lost carbon is proposed.

Full text of DOI:10.1021/acs.joc.7b00784

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Metal- and O2 Free Oxidative C-C Bond Cleavage of Aromatic Aldehydes
Guang Hu, Kinthada Ramakumar, and Stacey Ellen Brenner-Moyer
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 07 Jun 2017
Downloaded from http://pubs.acs.org on June 8, 2017
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Metal- and O2-Free Oxidative C-C Bond Cleavage of Aromatic Aldehydes
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Guang Hu,‡ Kinthada Ramakumar,‡ Stacey E. BrennerꢀMoyer*
Department of Chemistry, Rutgers University, 73 Warren Street, Newark, New
Jersey 07102
‡
These authors contributed equally.
seb244@rutgers.edu
Abstract
An oxidative CꢀC cleavage of aldehydes requiring neither metals nor O2 has
been discovered. Homobenzylic aldehydes and αꢀsubstituted homobenzylic
aldehydes were cleaved to benzylic aldehydes and ketones, respectively, using
nitrosobenzene as an oxidant. This reaction is chemoselective for aromatic
aldehydes, as an aliphatic aldehyde was unreactive under these conditions, and
other reactive functionality such as ketones and free alcohols are tolerated. A
mechanism accounting for the fate of the lost carbon is proposed.
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Aldehydes are one of the most versatile functional groups in organic
chemistry and, as such, aldehyde intermediates are frequently employed in
synthesis. Carbonꢀcarbon bond cleavage of aldehydes, although desirable to the
synthetic chemist, is difficult to achieve owing to the inherent stability of carbonꢀ
carbon bonds. Historically this has required the preformation of enamines, in
conjunction with strong metal oxidants.1ꢀ6 Although recent progress has allowed
for direct CꢀC cleavage of aldehydes, strong metal oxidants or metals in
combination with molecular oxygen or air are usually necessitated.7ꢀ14 Very
recently, however, metalꢀfree methods have emerged for the direct oxidative
carbonꢀcarbon bond cleavage of aldehydes. In situ enamine formation in the
presence of oxygen produced ketones (eq. 1, Scheme 1) or esters.15ꢀ17 To the
best of our knowledge, there is only one example of metalꢀ and oxygenꢀfree
oxidative carbonꢀcarbon bond cleavage of aldehydes. In this example, αꢀaryl
aldehydes were converted to aryl aldehydes or ketones using iodosylbenzene in
conjunction with a strong Brønsted or Lewis acid (eq. 2).18 Moreover, we
encountered only one example in the literature of carbonꢀcarbon bond cleavage
using nitrosobenzene.19 This method entailed the formation of enolates of
activated phenyl esters (i.e., βꢀdiesters and αꢀaryl esters), followed by reaction
with nitrosobenzene under cryogenic conditions to generate ketimines via an
oxazetidinꢀ4ꢀone intermediate (eq. 3). Reported herein is the serendipitous
discovery of the use of nitrosobenzene as a reagent to directly cleave carbonꢀ
carbon bonds of αꢀaryl aldehydes. In contrast to the methods illustrated in
Scheme 1, the method disclosed herein does not necessitate the use of high
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pressures of oxygen, strong Brønsted or Lewis acids, or cryogenic conditions.
As such, with its comparatively mild conditions and broad functional group
tolerance, this new method is amenable to providing benzylic aldehydes or aryl
ketones, for structureꢀactivity relationship (SAR) studies or relay synthesis, from
aromatic ringꢀcontaining natural products. Moreover, this method is proposed to
proceed via a novel mechanism that is distinct from that by which
nitrosobenzeneꢀmediated oxidative carbonꢀcarbon bond cleavage of esters is
reported to proceed.
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Scheme 1. Relevant examples of metal-free C-C bond cleavage.
Recently, we reported a dienamineꢀcatalyzed redox reaction between
enals, 7, and nitrosobenzene to yield γꢀnitrone products 9 (Scheme 2).20 The
products of this reaction could be readily transformed into heterocycles, 10 and
11, while still maintaining their aldehyde functionality, which could be elaborated
further.
Scheme 2. Reaction of α,β-unsaturated aldehydes with PhNO.
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We were curious to see whether this method could be extended to
saturated aldehydes to produce the corresponding αꢀnitrone products. Phenyl
acetaldehyde, 12a, was thus subjected to similar reaction conditions (entry 1,
Table 1). While a trace amount of the nitrone product, 13, was observed,
surprisingly the major identifiable product of the reaction was the product of
oxidative cleavage: benzaldehyde (14a).
Table 1. Key optimizations and control experiments.a
a
Reaction conditions: 12a, PhNO (4 equiv), additive, DCM (1 M), 24 h. b 1H
NMR yield using cyclohexene as internal standard. c Rigorous exclusion of O2 via
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freezeꢀpumpꢀthaw technique. d solvent = H2O. e 13 used instead of 12a. BHT =
butylated hydroxytoluene
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Seeking to learn more about this transformation, optimization and control
experiments were initiated. The yield of benzaldehyde doubled when the amine
additive was 4ꢀnitroaniline instead of 8 (entry 2). However, the reaction
proceeded nearly as well in the absence of an amine additive (entry 3). Thus,
the reaction does not, in fact, proceed via an enamine intermediate. Rather, the
low yield using 8 is possibly due to competing enamineꢀcatalyzed reactions,
whereas 4ꢀnitroaniline is likely too weakly nucleophilic to generate an enamineꢀ
species in the first place. Use of 2 equivalents of nitrosobenzene is sufficient for
this transformation, albeit slightly reduced product yields were obtained.21 After
extensive consideration of reaction variables including equivalents of
nitrosobenzene, solvent, additives, concentration, temperature, and time,21 the
conditions summarized in entries 3 and 4 were found to be optimal.
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The rigorous exclusion of O2 did not affect the reaction yield, affirming that
adventitious O2 is neither a catalyst nor reagent for this transformation (entry 5).
Addition of the radical inhibitor BHT did not suppress the reaction, verifying that a
radical mechanism is not operative (entries 6ꢀ7). While the addition of water was
tolerated, and water could be used as a reaction solvent, the rigorous exclusion
of water resulted in significantly lower product yields after 24 h (entries 8ꢀ10).
Water (and 4ꢀnitroaniline) may help to stabilize the reactive enol form of 12a
and/or activate nitrosobenzene via hydrogen bonding interactions (vide infra).
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Finally, subjecting 13 to the reaction conditions did not yield any benzaldehyde,
demonstrating that the nitrone is not an intermediate in this reaction (entry 11).
A variety of carbonyl compounds were evaluated under the reaction
conditions at both rt and at 50 °C, with only the isolated yield arising from the
optimal method for each substrate being reported in Scheme 3. The reaction
time was 24 hours, which compares favorably with the only existing metalꢀ and
oxygenꢀfree method for oxidative carbonꢀcarbon bond cleavage of aldehydes
(eq. 2, Scheme 1), which required 6 days to generate aldehyde products from 12
(R = H). Substituted benzaldehydes 14aꢀ14i were all formed in comparable
yields, regardless of the electronic nature or position of the substituent. Even
bulky 1ꢀnaphthaldehyde, 14j, was generated in a similarly moderate yield.
Heteroaromatic aldehydes, such as 14k, could also be generated using this
method. Interestingly, 3ꢀphenylpropanal produced 14a in 23% 1H NMR yield at rt,
while trace (<1%) 14a was formed when 4ꢀphenylbutanal was evaluated at rt.
Ketone products could be formed by subjecting αꢀsubstituted
homobenzylic aldehydes to the reaction conditions. In all cases, the higher
temperature of Method B was required for ketone formation, as yields of < 5%
were obtained at rt. Biaryl ketones 14l and 14o were produced in higher yields
than other aryl ketones 14m and 14n. Starting carbonyl compounds were
recovered from a homobenzylic ketone (1ꢀphenylꢀ2ꢀbutanone, 1,3ꢀdiphenylꢀ2ꢀ
propanone), acid (phenylacetic acid), and ester (methyl_phenylacetate), and from
a βꢀdicarbonyl compound (3ꢀbenzylꢀ2,4ꢀpentanedione) under the reaction
conditions.
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Importantly, whereas the only existing metalꢀ and oxygenꢀfree method for
oxidative carbonꢀcarbon bond cleavage of aldehydes utilizes a strong Brønsted
or Lewis acid (eq. 2, Scheme 1), our mild conditions are compatible with other
reactive functionalities. Most notably, this reaction is chemoselective for aromatic
aldehydes, for example no reaction was observed with an aliphatic aldehyde (2ꢀ
ethylhexanal) under these conditions. Additionally, a nucleophilic free alcohol
(14e) as well as a reactive ketone (14f) were tolerated.
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Scheme 3. Substrate scope.aꢀb
a
Reaction conditions: 12, PhNO (4 equiv), DCM (1 M), 24 h. Method A = rt.
b
c
Method B = 50 °C.
alcohol.
Yield = isolated yield.
Isolated yield of corresponding
It is envisioned that this method will facilitate access to benzylic aldehydes
and aryl ketones from complex homobenzylic aldehydes, for synthetic and
medicinal purposes. As an illustration of this application, diaryl ketone 14p was
furnished in 42% yield from homobenzylic aldehyde 12p (Scheme 4). Upon
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subjecting 12p to TBAF during the course of exploratory SAR studies on
combretastatin Aꢀ1, Pettit and coworkers serendipitously generated the
corresponding free alcohol of this diaryl ketone (15) in 49% yield.22
Combretastatin Aꢀ1 is a natural product possessing potent activity as both a
microtubule assembly inhibitor and as a sensitizer of multidrugꢀresistant cancer
cells to other chemotherapeutic agents.23ꢀ24 Diaryl ketone 15 was found to have
identical activity to combretastatin Aꢀ1 in inhibition assays of both cancer cell
growth and tubulin polymerization.25 In contrast to Pettit’s conditions, our
conditions do not require O2 and are orthogonal to silyl protecting groups, and
thus provide a more general method for producing benzylic aldehydes and aryl
ketones of interest from the corresponding homobenzylic aldehydes.
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Scheme 4. Synthetic utility.
A possible mechanism for this transformation is illustrated in Scheme 5.
Homobenzylic aldehyde 12a is in equilibrium with its enol tautomer, 16. The enol
tautomer of homobenzylic aldehydes should form more readily than that of
aliphatic aldehydes, as the enol tautomer of homobenzylic aldehydes contains a
π bond in conjugation with the aromatic ring. Enol 16 possesses a nucleophilic
αꢀcarbon, which can react with the electrophile, nitrosobenzene.
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Reaction of enol 16 with one equivalent of nitrosobenzene generates 17.
Due to the αꢀeffect, 17 contains a highly nucleophilic nitrogen atom that can react
with a second equivalent of nitrosobenzene to produce 18. Intramolecular (or
intermolecular) nucleophilic addition to the aldehyde initiates CꢀC bond cleavage,
affording benzaldehyde, 14a, along with byproducts azobenzene, 20, and formic
acid, 21. The driving force for bond cleavage is the formation of benzylic
aldehydes, which contain a carbonꢀoxygen π bond in conjugation with the
aromatic ring.
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Scheme 5. Possible mechanism.
The proposed mechanism is the culmination of several mechanistic
probes as well as literature precedence. First, there are numerous reports of Oꢀ
nitroso aldol reactions (i.e, 12aꢀ>17) catalyzed by chiral secondary amines, such
as 8.26ꢀ35
In almost all of these reactions, nitrosobenzene is used in
substoichiometric quantities,26ꢀ32,34ꢀ35 often in a 1:3 ratio with the aldehyde
reactants,26,28ꢀ30,32,34ꢀ35 possibly to avoid overoxidation products (i.e., 13 and 14a)
that can arise in the presence of stoichiometric (or greater) amounts of this
reagent. Moreover, in all of these reactions, the aldehyde products (i.e., 17) are
not isolated. Rather an in situ reduction is performed, and it is the corresponding
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alcohols that are isolated. It was, therefore, not possible for us to isolate 17 and
resubject it to our own reaction conditions to verify whether 14a is formed.
Instead, we reproduced one of these procedures,26 in which 12a was
reacted with 0.33 equiv of nitrosobenzene in CHCl3 using 5 mol % Lꢀproline as
catalyst. After 2 h, a new aldehyde peak and a small amount of benzaldehyde
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1
were observed by H NMR. An in situ reduction was performed, and the
corresponding alcohol of 17 was isolated in 60% yield, a quantity identical to that
reported for this substrate in this procedure.26
We then reran the reaction. After 2 h, again, a new aldehyde peak and a
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small amount of benzaldehyde were observed by H NMR. At this time, 3.67
equiv of nitrosobenzene were added to total the 4 equiv of nitrosobenzene that
are employed in our conditions. Subsequently, the disappearance of the
aldehyde peak corresponding to 17 and a dramatic increase in the aldehyde
peak corresponding to benzaldehyde were observed.
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experiments suggest that 17 is a plausible intermediate in the formation of 14a.
As mentioned above, due to the αꢀeffect, 17 contains a highly nucleophilic
nitrogen atom that can rapidly further react with nitrosobenzene.20 The reaction
of carbonyl compounds with 2 equiv of nitrosobenzene to form intermediates
related to 18 has been reported previously.20,33 These reports support the
possible intermediacy of 18 in this transformation.
Finally, the byproducts formic acid and azobenzene were observed by
various analytical methods. 1H NMR spectra of the crude reaction mixture
displayed a peak at 8.00 ppm, and a peak at 165.82 ppm was visible in crude 13C
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NMR spectra, corresponding to HA (Scheme 5) and the carbon in formic acid,
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respectively.21
Moreover, using ReactIR it was possible to observe the
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disappearance of the phenyl acetaldehyde (12a) carbonyl stretch peak at 1723
cmꢀ1 over time, and the emergence of peaks at 1704 cmꢀ1 and 1719 cmꢀ1,
corresponding to the carbonyl stretch frequencies of benzaldehyde and formic
acid, respectively (Figure 1). All 3 of these compounds were independently
subjected to ReactIR to verify these frequencies, and to verify that solutions of
these compounds obeyed Beer’s law at the reaction concentration.21 GCꢀMS
spectra of the crude reaction displayed a prominent peak at 182 m/z (tR = 13.63
min), corresponding to the mass of azobenzene.21 The identity of this peak was
confirmed by injection of commercially available pure azobenzene (tR = 14.04
min).
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Figure 1. ReactꢀIR analysis of the reaction of phenylacetaldehyde with PhNO in
dichloromethane at 0 (sea green), 8 (blue), 9 (green), 10 (orange) and 11 (pink)
hours.
Over time, phenylacetaldehyde (carbonyl vibration at 1723 cmꢀ1)
decreases, while benzaldehyde (1704 cmꢀ1) increases. Additionally, the slope of
the line from 1723 cmꢀ1 to 1719 cmꢀ1 changes over time with the emergence of a
peak at 1719 cmꢀ1, corresponding to the carbonyl vibration of formic acid.
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In conclusion, reported herein is a novel, mild, metalꢀ and O2ꢀfree method
for the oxidative carbonꢀcarbon bond cleavage of aldehydes. Under these
reaction conditions, nitrosobenzene selectively cleaves aromatic aldehydes; an
aliphatic aldehyde was unreactive under these conditions, and a readily
enolizable ketone and nucleophilic free alcohol were also tolerated. This reaction
seemingly proceeds via a mechanism that is distinct from that by which
nitrosobenzeneꢀmediated oxidative carbonꢀcarbon bond cleavage of esters is
reported to proceed. Because carbonꢀcarbon bond cleavage of aldehydes is a
highly desirable process for synthetic chemists, and because homobenzylic
aldehydes react orthogonally to other highly reactive functionality under these
mild conditions, this process may find utility in the synthesis of natural products
or medicinal compounds containing aromatic rings. Moreover, the ability of
nitrosobenzene to participate in a diverse array of chemical reactions via equally
diverse reaction mechanisms, warrants continued exploration into the use of this
versatile organic reagent in new synthetic transformations.
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Experimental Section
General Information
NMR data were acquired on a 500 MHz NMR spectrometer and use the following
abbreviations: s = singlet, d = doublet, t = triplet, m = multiplet, dd = doublet of
doublets, ddd = doublet of doublets of doublets, brm = broad multiplet, brs =
broad singlet. HRMS spectra were acquired using an MS spectrometer with Qꢀ
TOF mass analyzer. Flash chromatography was carried out with F60, 40−63
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mm, 60 Å silica gel and EMD silica 60 F254 glass TLC plates. Solvents were
dried and kept airꢀfree in a solvent purification unit, and were evaporated using a
standard rotovapor and high vacuum. All reactions were carried out in oven dried
glassware. Phenyl acetaldehydes were prepared according to literature
procedures.18,36
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General procedure
A: Phenyl acetaldehyde (60.07 mg, 0.5 mmol) and nitrosobenzene (214.22 mg,
2.0 mmol) were dissolved in dichloromethane (0.5 mL, 1 M) in a capped vial and
stirred at rt for 24 hours, then the reaction mixture was passed through flash
column chromatography using EtOAc/hexane and the products were isolated.
B: Phenyl acetaldehyde (60.07 mg, 0.5 mmol) and nitrosobenzene (214.22 mg,
2.0 mmol) were dissolved in dichloromethane (0.5 mL, 1 M) in a sealed tube and
heated at 50 °C for 24 hours, then the reaction mixture was passed through flash
column chromatography using EtOAc/hexane and the products were isolated.
Compound characterization data:
benzaldehyde (14a):37 Prepared following procedure A and purified by column
chromatography using 1:9 EtOAc/hexane and isolated as a colorless liquid (32
1
mg, 61%): H NMR (500 MHz, CDCl3) δ 10.03 (s, 1H), 7.91 – 7.87 (m, 2H), 7.64
(t, J = 7.4 Hz, 1H), 7.54 (t, J = 7.6 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 192.4,
136.4, 134.5, 129.7, 129.0. HRMS (EI): exact mass calculated for [MꢀH]ꢀ
(C7H5O1) requires m/z 105.0340, found m/z 105.0338.
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4-methoxybenzaldehyde (14b):37 Prepared following procedure A and purified
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by column chromatography using 1:9 EtOAc/hexane and isolated as an orange
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liquid (45 mg, 67%): H NMR (500 MHz, CDCl3) δ 9.88 (s, 1H), 7.84 (d, J = 8.4
Hz, 2H), 7.00 (d, J = 8.4 Hz, 2H), 3.89 (s, 3H).13C NMR (126 MHz, CDCl3) δ
190.8, 164.6, 132.0, 130.0, 114.3, 55.6. HRMS (ESI): exact mass calculated for
[M]+ (C8H8O2) requires m/z 136.0524, found m/z 136.0526.
4-chlorobenzaldehyde (14c):37 Prepared following procedure A and purified by
column chromatography using 1:9 EtOAc/hexane and isolated as a yellow solid
(44 mg, 63%): mp 50 °C 1H NMR (500 MHz, CDCl3) δ 10.01 (s, 1H), 7.85 (d, J =
7.2 Hz, 2H), 7.54 (d, J = 7.5 Hz, 2H). 13C NMR (125 MHz, CDCl3) δ 190.84,
141.0, 134.7, 130.9, 129.5. HRMS (EI): exact mass calculated for [MꢀH]ꢀ
(C7H4OCl) requires m/z 138.9951, found m/z 138.9950.
4-nitrobenzaldehyde (14d):37 Prepared following procedure A and purified by
column chromatography using 1:9 EtOAc/hexane and isolated as an orange solid
(36 mg, 48%): mp 103 °C 1H NMR (500 MHz, CDCl3) δ 10.15 (s, 1H), 8.37 (d, J =
8.4 Hz, 2H), 8.07 (d, J = 8.3 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 190.4, 151.1,
140.1, 130.5, 124.3. HRMS (EI): exact mass calculated for [M]+ (C7H5NO3)
requires m/z 151.0269, found m/z 151.0269.
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4-hydroxybenzaldehyde (14e):38 Prepared following procedure A and purified
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powder (33 mg, 54%): mp 114 °C H NMR (500 MHz, CDCl3) δ 9.86 (s, 1H),
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7.81 (d, J = 7.4 Hz, 2H), 6.97 (d, J = 8.0 Hz, 2H), 6.30 (brs, 1H). C NMR (126
MHz, CDCl3) δ 191.1, 161.5, 132.5, 130.0, 116.0. HRMS (ESI): exact mass
calculated for [M]+ (C7H6O2) requires m/z 122.0368, found m/z 122.0371.
4-acetylbenzaldehyde (14f):39 Prepared following procedure A and purified by
column chromatography using 1:9 EtOAc/hexane and isolated as an orange
1
liquid (45 mg, 63%): H NMR (500 MHz, CDCl3) δ 10.09 (s, 1H), 8.08 (d, J = 7.8
Hz, 2H), 7.96 (d, J = 7.8 Hz, 2H), 2.65 (s, 3H). 13C NMR (126 MHz, CDCl3) δ
197.4, 191.6, 141.2, 139.1, 129.8, 128.8, 27.0. HRMS (EI): exact mass
calculated for [M]+ (C9H8O2) requires m/z 148.0524, found m/z 148.0529.
2-methylbenzaldehyde (14g):40 Prepared following procedure B and purified by
column chromatography using 1:9 EtOAc/hexane and isolated as a colorless
1
liquid (40 mg, 60%): H NMR (500 MHz, CDCl3) δ 10.30 (s, 1H), 7.82 (d, J = 7.6
Hz, 1H), 7.50 (t, J = 7.4 Hz, 1H), 7.38 (t, J = 7.5 Hz, 1H), 7.28 (d, J = 7.5 Hz, 1H),
2.70 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 192.7, 140.5, 134.1, 133.6, 132.0,
131.7, 126.3, 19.5. HRMS (EI): exact mass calculated for [M]+ (C8H8O) requires
m/z 120.0575, found m/z 120.0576.
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3-methoxybenzaldehyde (14i):37 Prepared following procedure A and purified
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liquid (45 mg, 66%): H NMR (500 MHz, CDCl3) δ 10.00 (s, 1H), 7.51 – 7.45 (m,
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2H), 7.42 (s, 1H), 7.20 (d, J = 6.7 Hz, 1H), 3.89 (s, 3H). 13C NMR (125 MHz,
CDCl3) δ 192.1, 160.1, 137.8, 130.0, 123.5, 121.5, 112.0, 55.4. HRMS (EI): exact
mass calculated for [M]+ (C8H8O2) requires m/z 136.0524, found m/z 136.0526.
1-naphthaldehyde (14j):37 Prepared following procedure B and purified by
column chromatography using 1:19 EtOAc/hexane and isolated as a yellow liquid
1
(45 mg, 58%): H NMR (500 MHz, CDCl3) δ 10.44 (s, 1H), 9.28 (d, J = 8.5 Hz,
1H), 8.13 (d, J = 8.1 Hz, 1H), 8.03 (d, J = 6.8 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H),
7.72 (t, J = 7.5 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.61 (t, J = 7.4 Hz, 1H). 13C NMR
(125 MHz, CDCl3) δ 193.5, 136.7, 135.3, 133.7, 131.4, 130.6, 129.1, 128.5,
127.0, 124.9. HRMS (EI): exact mass calculated for [M]+ (C11H8O) requires m/z
156.0575, found m/z 156.0577.
benzofuran-2-carbaldehyde (14k):41 Prepared following procedure A and
purified by column chromatography using 1:19 EtOAc/hexane and isolated as a
1
yellow liquid (34 mg, 47%): H NMR (500 MHz, CDCl3) δ 9.88 (s, 1H), 7.76 (d, J
= 7.9 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.57 (s, 1H), 7.53 (t, J = 7.8 Hz, 1H), 7.35
(t, J = 7.5 Hz, 1H).13C NMR (126 MHz, CDCl3) δ 179.8, 156.3, 152.8, 129.2,
126.7, 124.2, 123.7, 117.7, 112.76. HRMS (ESI): exact mass calculated for
[M+H]+ (C9H7O2) requires m/z 147.0446, found m/z 147.0445.
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benzophenone (14l):18 Prepared following procedure B and purified by column
chromatography using 1:99 EtOAc/hexane and isolated as a white solid (62 mg,
68%): mp 47 °C 1H NMR (500 MHz, CDCl3) δ 7.81 (d, J = 7.7 Hz, 4H), 7.59 (t, J
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= 7.3 Hz, 2H), 7.49 (t, J = 7.5 Hz, 4H).13C NMR (126 MHz, CDCl3) δ 196.8,
137.6, 132.4, 130.1, 128.3. HRMS (ESI): exact mass calculated for [M+H]+
(C13H11O) requires m/z 183.0810, found m/z 183.0814.
acetophenone (14m):18 Prepared following procedure B and purified by column
chromatography using 1:19 EtOAc/hexane and isolated as a colorless liquid (24
1
mg, 40%): H NMR (500 MHz, CDCl3) δ 7.96 (d, J = 7.9 Hz, 2H), 7.59 – 7.54 (m,
1H), 7.46 (t, J = 7.4 Hz, 2H), 2.61 (s, 3H).13C NMR (126 MHz, CDCl3) δ 198.2,
137.2, 133.1, 128.6, 128.3, 26.6. HRMS (EI): exact mass calculated for [M]+
(C8H8O) requires m/z 120.0575, found m/z 120.0575.
3,4-dihydronaphthalen-1(2H)-one (14n):18 Prepared following procedure B and
purified by column chromatography using 1:9 EtOAc/hexane and isolated as an
orange liquid (22 mg, 30%): 1H NMR (500 MHz, CDCl3) δ 8.04 (d, J = 7.8 Hz,
1H), 7.47 (t, J = 7.3 Hz, 1H), 7.31 (t, J = 7.5 Hz, 1H), 7.26 (d, J = 7.6 Hz, 1H),
2.97 (t, J = 5.8 Hz, 2H), 2.66 (t, J = 6.4 Hz, 2H), 2.16 – 2.13 (m, 2H). 13C NMR
(125 MHz, CDCl3) δ 198.2, 144.4, 133.3, 132.5, 128.7, 127.0, 126.5, 39.1, 29.6,
23.2. HRMS (ESI): exact mass calculated for [M+H]+ (C10H11O) requires m/z
147.0810, found m/z 147.0816.
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9H-fluoren-9-one (14o):18 Prepared following the procedure B, purified by
column chromatography using 1:99 EtOAc/hexane and isolated as a yellow solid
(41 mg, 45%). 1H NMR (500 MHz, CDCl3) δ 7.61 (d, J = 7.2 Hz, 2H), 7.44 (t, J =
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7.0 Hz, 4H), 7.25 (t, J = 7.0 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 193.9, 144.4,
134.7, 134.1, 129.1, 124.3, 120.3.
(2,3-bis((tert-butyldimethylsilyl)oxy)-4-methoxyphenyl)(3,4,5-
trimethoxyphenyl)methanone (14p): To a solution of TBSꢀprotected Eꢀ
combretastatin Aꢀ1 (112 mg, 0.2 mmol) in acetone (1 mL) and H2O (40 ꢀL), was
added NMO (44 mg, 0.36 mmol) followed by tꢀBuOH (132 ꢀL). The solution was
cooled to 0 ºC and stirred for 5 minutes. OsO4 (4% in H2O, 0.2 mL, 0.024 mmol)
was added dropwise and the reaction stirred at 0 ºC for 15 minutes. The reaction
was brought to room temperature and stirred until complete consumption of
olefin, as observed by TLC. The reaction was quenched with a 10% solution of
Na2S2O3 and extracted with EtOAc (3 x 20 mL). The combined organic layers
were washed with brine and dried over Na2SO4.
The crude diol was
concentrated under reduced pressure and purified by flash chromatography
(30% EtOAc:petroleum ether) to obtain pure diol (107 mg, 90%).
.
BF3 OEt2 (45ꢀL, 0.358 mmol) was added dropwise to a stirred solution
of diol (107 mg, 0.179 mmol) in anhydrous THF (2.5 mL) under argon at room
temperature for 1.5 h. The reaction was quenched with saturated NaHCO3 (aq.)
and extracted with EtOAc (3 x 20 mL). The combined organic layers were
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washed with brine and dried over Na2SO4. The crude aldehyde was concentrated
under reduced pressure and purified by flash chromatography (10%
EtOAc:petroleum ether) to obtain pure aldehyde 12p as an oil (74 mg, 72%).
Aldehyde 12p (23 mg, 0.04 mmol) and nitrosobenzene (17 mg, 0.16
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mmol) were dissolved in dichloromethane (0.040 mL, 1 M) in a sealed tube and
heated at 80 °C for 10 hours, then the reaction mixture was directly purified by
flash chromatography (8% EtOAc:petroleum ether) to obtain pure 14p as a
1
yellow liquid (10 mg, 42%). H NMR (500 MHz, CDCl3) δ 7.12 (s, 2H), 7.05 (d, J
= 8.4 Hz, 1H), 6.64 (d, J = 8.5 Hz, 1H), 3.89 (s, 3H), 3.84 (s, 9H), 1.01 (s, 9H),
0.66 (s, 9H), 0.17 (s, 6H), ꢀ0.02 (s, 6H). 13C NMR (126 MHz, CDCl3) δ 194.9,
154.5, 152.8, 145.6, 142.4, 137.0, 133.3, 126.5, 123.1, 108.0, 105.2, 61.0, 56.2,
55.1, 26.1, 25.8, 18.8, 18.0, ꢀ3.5, ꢀ3.8. HRMS (ES+): exact mass calculated for
[M+H]+ (C29H47O7Si2) requires m/z 563.2860, found m/z 563.2856.
(2-(trifluoromethyl)phenyl)methanol (22h):42 Prepared following procedure B
and further reduced by NaBH4 and purified by column chromatography using 1:9
EtOAc/hexane and isolated as an orange liquid (58 mg, 66% over 2 steps): 1H
NMR (500 MHz, CDCl3) δ 7.71 (d, J = 7.6 Hz, 1H), 7.64 (d, J = 7.7 Hz, 1H), 7.57
(t, J = 7.5 Hz, 1H), 7.38 (t, J = 7.5 Hz, 1H), 4.87 (s, 2H), 2.16 (brs, 1H). 13C NMR
(126 MHz, CDCl3) δ 139.3, 132.2, 128.8, 127.5, 127.2 (q, 3J(C,F)=30.8 Hz) 125.8
1
2
4
(q, J(C,F)=5.7 Hz), 124.4 (q, J(C,F)=5.7 Hz), 61.4 (q, J(C,F)=2.9 Hz). HRMS
(ESI): exact mass calculated for [M+H]+ (C8H8F3O) requires m/z 177.0522, found
m/z 177.0512.
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Acknowledgments
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This work was supported by the National Science Foundation (CAREERꢀ
1461919) and by Rutgers University. The Bruker 500 MHz spectrometer used in
these studies was furnished by an NSFꢀMRI grant (CHEꢀ1229030). The authors
are grateful to Prof. Agostino Pietrangelo (Rutgers University) and Rajani Bhat
(Rutgers University) for granting access to, and assistance operating, the
ReactIR instrument, and for thoughtful discussion pertaining to the ReactIR
experiments. The authors also gratefully acknowledge Dr. Roman Brukh
(Rutgers University) and Dr. Furong Sun (University of Illinois) for their
assistance with the acquisition of mass spectrometry data.
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Supporting Information
Further details about reaction optimization and mechanistic studies, and copies
of 1H and 13C NMR spectra.
References and Endnotes
1 Slomp, G.; Shealy, Y. F.; Johnson, J. L.; Donia, R. A.; Johnson, B. A.; Holysz, R.
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