The Conversion of tert-Butyl Esters to Acid Chlorides Using Thionyl Chloride

Article abstract of DOI:10.1021/acs.joc.6b02931

The reaction of tert-butyl esters with SOCl₂ at room temperature provides acid chlorides in unpurified yields of 89% or greater. Benzyl, methyl, ethyl, and isopropyl esters are essentially unreactive under these conditions, allowing for the selective conversion of tert-butyl esters to acid chlorides in the presence of other esters.

Full text of DOI:10.1021/acs.joc.6b02931

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Note
The Conversion of tert-Butyl Esters to Acid Chlorides Using Thionyl Chloride
Jacob Arthur Greenberg, and Tarek Sammakia
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02931 • Publication Date (Web): 14 Feb 2017
Downloaded from http://pubs.acs.org on February 15, 2017
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The Conversion of tert-Butyl Esters to Acid Chlorides Using Thionyl Chloride
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Jacob A. Greenberg and Tarek Sammakia*
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Department of Chemistry and Biochemistry, University of Colorado Boulder, Boulder, Colorado
80309, United States
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Corresponding author e-mail address: Sammakia@colorado.edu
Abstract:
O
O
SOCl2, H2O
room temp
R
O
R
Cl
O
SOCl2, H2O
room temp
No
Reaction
R
OR1
R1= methyl, ethyl, isopropyl, benzyl
The reaction of tert-butyl esters with SOCl2 at room temperature provides acid chlorides in
unpurified yields of 89% or greater. Benzyl, methyl, ethyl, and isopropyl esters are essentially
unreactive under these conditions, allowing for the selective conversion of tert-butyl esters to
acid chlorides in the presence of other esters.
Acid chlorides are useful intermediates often used as active esters for the synthesis of
carboxylic acid derivatives. They are commonly prepared via the corresponding carboxylic acids
which are treated with a chlorinating agent such as SOCl2, PCl5, POCl3, oxalyl chloride,
phosgene, cyanuric chloride, activated triphenylphosphine reagents, and α,α-dichloro ethers,
among others.1 The reaction can be catalyzed by the addition of DMF to generate the Vilsmeier-
Haack reagent,2 which serves as the active chlorinating agent. Other than the widely known
conversion of carboxylic acids to acid chlorides there are relatively few instances in the literature
of other functional group transformations that can yield acid chlorides directly. Examples include
the conversion of lactones,3 a few tert-butyl esters,4 ethyl chlorofluoroacetate, 5 and tert-
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butyldimethylsilyl esters,6 to the corresponding acid chlorides. In this note, we describe the use
of SOCl2 and water or HCl for the conversion of tert-butyl esters to acid chlorides in high yields.
This study originated from a need to prepare an acid chloride wherein the corresponding
carboxylic acid was difficult to isolate. However, the tert-butyl ester was available, and we
therefore decided to study the direct conversion of tert-butyl esters to acid chlorides. We began
with a model substrate, tert-butyl dihydrocinnamate (1a), and studied a variety of conditions for
its conversion dihydrocinnamoyl chloride (2a) as described in Table 1. We ran the reaction at
room temperature, either in sealed vials or open to the atmosphere, and with or without water or
2,6-di-tert-butyl-4-methylpyridine. In the absence of water, the reaction requires 16 h to proceed
to high conversion (Table 1, entries 1 and 2). In the presence of water, which presumably reacts
with SOCl2 to provide HCl and SO2, the reaction proceeds to completion in 30 min when sealed
(Table 1, entry 4). On larger scale, sealed vessels are less convenient, and as such we studied
reactions open to the atmosphere and with water as an additive (Table 1, entries 5-7). These
reactions were qualitatively slower, requiring 16 h to proceed to completion. We attribute the
decreased rate of reactions in open vessels to the loss of HCl from the mixture, leading to lower
concentrations of acid than in sealed vessels from which the HCl cannot escape.7 This reaction is
amenable to scale up and provides similar results on 20 mmol scale when conducted open to the
atmosphere in the presence of 1 equiv HCl (a concd aqueous solution was used; 91% yield after
purification by distillation; see Table 1, entry 7).
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Table 1. Optimization of tert-Butyl Ester to Acid Chloride Conditions
O
O
SOCl2
Ot-Bu
Cl
1a
2a
Entry Conditionsa
Time Yieldb
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1
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Sealed, no additives
Sealed, no additives
0.5 h 9%c
16 h 83%
16 h 0%c
Sealed, 2,6-di-tert-
butyl-4-
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methylpyridine
4
5
6
7
Sealed, H2O
Open, H2O
Open, H2O
Open, HCl, 20 mmol
scale
0.5 h 91%
1 h
60%c
16 h 90%
16 h 91%d
aSealed reactions were performed in 2 dram (7.4 mL) vials containing a stir bar and capped with
a teflon-lined cap. The ester (0.5 mmol, 1 equiv) was dissolved in SOCl2 (5.0 mmol, 10 equiv),
treated with additive (1 equiv), then sealed (or left open as indicated) and stirred for the time
specified. The vials were then carefully opened, and SOCl2 was removed via azeotropic
distillation (2x) with toluene. bYield refers to isolated crude product unless otherwise indicated.
cPercent conversion was calculated from the ratio of Product:SM by 1H NMR. dYield refers to
product isolated after vacuum distillation; 1 equiv of HCl and 20 equiv SOCl2 were used in this
experment.
We considered two mechanistic options for this reaction, one in which the ester carbonyl
is activated by SOCl2 via complexation followed by loss of tert-butyl cation (Scheme 1, path A),
the other in which the ester carbonyl is protonated, also resulting in loss of tert-butyl
cation (Scheme 1, path B).8 The resulting intermediates would then undergo chlorination with
either HCl (path A) or SOCl2 (path B). The addition of 2,6-di-tert-butyl-4-methylpyridine can
distinguish between these mechanisms. In the presence of this reagent, no reaction is observed
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after 16 h (Table 1, entry 3), suggesting that HCl is playing a crucial role in the reaction,
consistent with path B. We note that this is mechanistically distinct from the SOCl2-mediated
chlorination of lactones, first described by Harris and Molander, which likely proceeds via an
SN2 pathway to provide a chloro-acid, such as 3, that subsequently undergoes chlorination
(Scheme 1, path C).3
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Scheme 1. Possible Mechanistic Pathways
O
O
Path A
SOCl2
S
HCl
S
Cl
O
O
Cl
R
O
O
R
O
O
R
O
R
Cl
OH
OH
SOCl2
O
Path B
H
R
O
R
O
Harris and Molander:
O
OH
O
SOCl2
Path C
HO
Cl
RO
RO
O
O
Cl
HCl
OR Cl
3
OR Cl
We then synthesized the methyl, ethyl, isopropyl, and benzyl dihydrocinnamate esters
and studied each using the optimized reaction conditions for tert-butyl esters (H2O, sealed vials,
0.5 h), as well as with extended reaction times to 16 h. We observed no conversion to product
with all the esters, except benzyl, which provided 1% product after 16 h (Table 2, entry 1-4).
These results show that the reaction is highly selective for tert-butyl esters under our conditions.
Table 2. Ester Selectivity with Optimized tert-Butyl Ester Conditionsa
O
O
SOCl2, H2O
OR
Cl
room temp
entry
R
Conversion Conversionb
at 30 min
NR
at 16 h
NR
1
2
Me (4)
Et (5)
NR
NR
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3
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i-Pr (6)
Bn (7)
NR
NR
NR
1%
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aSee Table 1 for conditions. bConversion was calculated from the ratio of Product:SM as
determined by 1H NMR.
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The scope of this method was studied using the substrates shown in Table 3. Acid
chlorides can be prepared from electron poor and electron rich aryl tert-butyl esters (2b-j) as
well as from functionalized aliphatic tert-butyl esters (2a, 2k-s); however, several substrates
required extended reaction times for complete conversion at room temperature (2b-j, 2p-s). We
found that electron deficient substrates (p-acetyl benzoate and p-nitro benzoate esters 2i and 2j),
provided the corresponding carboxylic acid at room temperature, and required heating to 100 °C
in toluene to provide acid chloride. We found the reaction conditions are also compatible with
terminal olefins, phthalate protected amino acids, and an acetyl functional group (Table 3, 1m-
o).
We wanted to study the stereochemical integrity of stereocenters a-to the carbonyl and
prepared compound 1m derived from D-valine. This compound was subjected to our reaction
conditions to provide acid chloride 2m, which was then converted to the corresponding methyl
ester (3m; methanol, 10 equiv; Hünigs base, 1.5 equiv; DCM) and observed the product in a 98.4
to 1.6 ratio of enantiomers, indicating that there is minimal erosion of stereochemistry at the a-
center in this substrate. We note that the subjection of γ-hydroxy ester 1t to SOCl2 provides the
corresponding lactone (Table 4, entry 1), suggesting that acid chloride formation and
lactonization is faster than chlorination of the starting alcohol or the product lactone. Protection
of the alcohol 1t as benzyl or silyl ethers also provided the lactone (Table 4, entry 2-5); however,
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protection as the tosylate, pivalate, or CBZ or Fmoc carbonate provides the desired acid
chlorides in good yields (Table 3, 2p-s).
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Table 3. Scope of Chlorination of tert-Butyl Estersa,b
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SOCl2, H2O
O
O
R
Ot-Bu
R
Cl
2a-m
1a-s
O
O
O
O
Cl
2b, 90%c
Cl
Cl
Ph
Cl
F
F
2d, 90%d
Cl
2c, 92%c
2a, 91%
O
O
O
O
O
MeO
Cl
Cl
Ph
Cl
AcO
Br
2e, 95%d
OMe
2f, 94%d
2h, 90%c
2g, 89%d
O
O
O
Cl
Ph
Cl
Cl
Cl
O
Cl
2k, 90%
OAc O
Ph
O2
N
e
2j, 93%e
2i, 95%
O
2l, 91%
Me
O
Me
Cl
O
Cl
Me
N
Cl
3
O
Cl
O
O
2m, 95%f
2n, 92%
2o, 98%
2p R= Ts
91%c
91%d
OR
Cl
2q R= Cbz
2r R= Fmoc 94%d
O
2s R= Piv
95%d
Cl
aSee Table 1 for conditions. bYields are of isolated products without further purification.
cReaction was stirred at 23 °C for 5 h. dReaction was stirred at 23 °C for 16 h. eReaction was
performed in toluene (0.1 M) in a sealed 2 dram (7.4 mL) vial at 100 °C for 16 h. fCompound 2m
was converted to methyl ester 3m for HPLC analysis.
Table 4. Sequential Chlorination, Deprotection, and Lactonizationa
OR
SOCl2, H2O
O
O
room temp
O
O
Cl
Cl
1n-r
8
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Entry
Compound R=
Yieldb
98%
84%
97%
97%
94%
1
2
3
4
5
1t
H
1u
1v
1w
1x
TES
TBS
TIPS
Bn
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aSee Table 1 for conditions. bYields are of isolated products without further purification.
We wished to confirm the selective conversion of tert-butyl esters in the presence of
other esters and performed competition experiments between substrates bearing tert-butyl esters,
and either a lactone, a methyl ester, or a benzyl ester (Scheme 2). In all cases, we obtained
complete conversion of the tert-butyl ester substrates with no observed acid chloride from the
lactone, methyl, or benzyl ester substrates.
Scheme 2. Competition experimentsa,b
O
SOCl2, H2O
16 h
+
Ot-Bu
Cl
O
Cl
O
O
1g
8
2g
(unreactive)
O
O
O
SOCl2, H2O
16 h
+
R
Ot-Bu
1a
OMe
OBn
R
Cl
9
2a
(unreactive)
O
Ot-Bu
Cl
SOCl2, H2O
30 min
+
R
O
O
Cl
Cl
2c
7
1f
(unreactive)
R= Dihydrocinnamyl
aSee Table 1 for conditions. bConversion was determined by 1H NMR.
In conclusion, we describe a simple and efficient method for the conversion of tert-butyl
esters to acid chlorides on a variety of substrates. Our mechanistic studies suggest that the
reaction is promoted by acid, and competition experiments show that the reaction is selective for
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tert-butyl esters in the presence of methyl, 1°, or 2° esters, and lactones. This method is mild and
compatible with other functional groups including alkenes, methyl ethers, protected amines,
sulfonates, carbonates, and acetate groups, and provides an alternative to other commonly used
methods for acid chloride synthesis.
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Experimental Section:
General Information. All reactions were carried out in flame dried glassware under a dry
nitrogen atmosphere or sealed in 2 dram (7.4 mL) vials with teflon lined caps as indicated. DCM,
diisopropylamine, methanol, ethanol, and isopropanol were distilled from CaH2 under nitrogen
and stored over 3Å molecular sieves prior to use. THF was distilled from Na benzophenone ketyl
under nitrogen prior to use. All other reagents were used as received from the supplier. Flash
chromatography was performed using 60Å silica gel (40-63 µm). 1H NMR spectra were recorded
at 300, 400, or 500 MHz in CDCl3 using residual CHCl3 (7.26 ppm) as an internal reference. 13C
NMR spectra were recorded at 75 or 100 MHz in CDCl3 using the center line of the CDCl3
triplet (77.16 ppm) as an internal reference. Infrared (IR) spectra were obtained as thin films on
NaCl plates. Exact mass was determined using electrospray ionization (ESI-TOF). We note that
in the case of several of the acid chlorides, the corresponding lithiated anhydride is present in the
HRMS spectrum and data is provided for the [M-Cl]+ ion. This ion could be derived from the
acid chloride or from the anhydride. In the cases where we report [M-Cl]+, we were unable to
observe the metalated (either lithiated or sodiated) acid chloride, or in some cases to find
conditions wherein [M-Cl]+ is the major ion in the spectrum. We attribute this to the reactive
nature of the acid chloride functional group, and the fact that the injection solvent is acetonitrile.
This solvent was rigorously dried prior to use, but as it is hygroscopic, it can absorb water as it is
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being used in the MS experiment. Compounds 1a,9 1b,9 1i,9 1k,10 4,11 5,12 6,13 7,14 9,15 were
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synthesized according to published procedures.
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General procedure for the synthesis of tert-butyl esters:9 The starting carboxylic acid (5
mmol; 1 equiv) was dissolved in DCM (12.5 ml; 0.25 M) and MgSO4 (20 mmol; 4 equiv) was
added. The flask was then purged with N2 and concd sulfuric acid (4.75 mmol; 0.95 equiv) was
added to the suspension followed by tert-butanol (25 mmol; 5 equiv). The suspension was
allowed to stir overnight at room temperature. The reaction was quenched by the addition of
hexanes/EA (1:1; ~50 mL) followed by saturated NaHCO3 (~50 mL; gas evolution!). The layers
were separated and the organic layer was washed with water (~50 mL; 2x), brine, then dried over
MgSO4. The reaction was filtered and concentrated under reduced pressure to provide the crude
product as a colorless oil. The crude product was purified by flash chromatography (10:1
hexanes/EA).
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tert-Butyl 2-Fluorobenzoate (1c) This compound was prepared according to the general
procedure to provide 1c (0.835g, 59%). 1H and 13C NMR are in accord with those reported in the
literature.16
tert-Butyl 4-Fluorobenzoate (1d) This compound was prepared according to the general
procedure to provide 1d (1.033g, 75%). 1H and 13C NMR are in accord with those reported in the
literature.16
tert-Butyl 2-Bromobenzoate (1e). This compound was prepared according to the general
procedure to provide 1e (1.452 g, 85%). 1H and 13C NMR are in accord with those reported in
the literature.17
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tert-Butyl 3,5-Dimethoxybenzoate (1f). This compound was prepared according to the general
procedure, to provide 1f (0.579 g, 43%) as a white amorphous powder. Rf = 0.40 (10:1
heanes/EA); 1H NMR (500 MHz, CDCl3) δ 7.16 (d, J = 2.4 Hz, 2H), 6.63 (t, J = 2.4 Hz, 1H),
3.84 (s, 6H), 1.60 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 165.5, 160.5, 133.9, 107.0, 105.0, 81.2,
55.5, 28.1. IR (thin film): C=O, 1713; HRMS (TOF-ESI) m/z calc’d for C13H18O4 [M+ H]+,
239.1283; found, 239.1283.
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tert-Butyl 4-Acetoxybenzoate (1g). Under a nitrogen atmosphere, tert-butyl 4-hydroxybenzoate
(0.642g, 3.30mmol, 1 equiv. prepared in 1 step following a known procedure)18 was dissolved in
THF-pyridine (1:1, 33 mL) and cooled to 0 °C. Acetyl chloride (0.258 mL, 3.63 mmol, 1.1
equiv) was added dropwise over 15 minutes. A white precipitate forms upon addition. The
reaction was allowed to warm to room temperature for 16 h until found to be complete by TLC.
Reaction was diluted with hexanes/EA (1:1) and subsequently washed with water (2x), followed
by brine, then dried over MgSO4. The reaction was filtered and concentrated to provide 1g
(0.775g, 99% yield) as a yellow oil. Rf = 0.34 (10:1 hexanes/EA); 1H NMR (400 MHz, CDCl3) δ
8.03 (d, J = 8.7 Hz, 2H), 7.15 (d, J = 8.7 Hz, 2H), 2.32 (s, 3H), 1.60 (s, 9H); 13C NMR (101
MHz, CDCl3) δ 169.0, 165.0, 154.0, 131.0, 129.7, 121.5, 81.2, 28.2, 21.2; IR (thin film): C=O,
1763, 1714 cm-1; HRMS (TOF-ESI) m/z calc’d for C13H16O4 [M+Li]+, 243.1209; found,
243.1212.
tert-Butyl 2-Benzoylbenzoate (1h). This compound was prepared according to the general
procedure to provide 1h (1.078 g, 86%) as a pale yellow amorphous solid. Rf = 0.34 (10:1
hexanes/EA); 1H NMR (500 MHz, CDCl3) δ 8.06 – 8.00 (m, 1H), 7.82 – 7.77 (m, 2H), 7.60-7.55
(m, 1H), 7.60 – 7.55 (m, 2H), 7.48 – 7.43 (m, 2H), 7.42 – 7.37 (m, 1H), 1.24 (s, 9H). 13C NMR
(101 MHz, CDCl3) δ 196.7, 165.2, 140.9, 137.2, 133.1, 132.0, 131.1, 129.9, 129.6, 129.6, 128.5,
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127.6, 82.6, 27.4. IR (thin film): C=O, 1714, 1674 cm-1; HRMS (TOF-ESI) m/z calc’d for
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C18H18O3 [M+Li]+, 289.1416; found, 289.1404.
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tert-Butyl 4-Acetylbenzoate (1j). This compound was prepared according to the general
procedure to provide 1j (0.645 g, 48%) as a white amorphous powder. 1H and 13C NMR are in
accord with those reported in the literature.19
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tert-Butyl 2,2-Diphenylacetate (1l). This compound was prepared according to the general
procedure to provide 1l (0.588 g, 46%) as a white amorphous solid. 1H and 13C NMR are in
accord with those reported in the literature.20
(R)-tert-Butyl 2-(1,2-Dioxoisoindolin-2-yl)-3-methylbutanoate (1m). This compound was
prepared according to the general procedure to provide 1m (0.823 g, 64%) as a white amorphous
solid. [α] = 28.2° Rf = 0.32 (10:1 hexanes/EA); 1H NMR (500 MHz, CDCl3) δ 7.88 (dd, J = 5.4,
3.1 Hz, 2H), 7.75 (dd, J = 5.5, 3.0 Hz, 2H), 4.51 (d, J = 8.2 Hz, 1H), 2.75 (dhept, J = 8.2, 6.8 Hz,
1H), 1.43 (s, 9H), 1.15 (d, J = 6.7 Hz, 3H), 0.92 (d, J = 6.8 Hz, 3H); 13C NMR (101 MHz,
CDCl3) δ 167.9, 167.8, 134.0, 131.7, 123.4, 82.2, 58.6, 28.5, 27.9, 21.0, 19.6; IR (thin film):
C=O, 1778, 1720 cm-1; [α] = 28.2°; HRMS (TOF-ESI) m/z calc’d for C17H21NO4 [M+Na]+,
326.1368; found 326.1370.
tert-Butyl 5-Acetoxy-6-oxoheptanoate (1n). 2-Methylcyclohex-2-enyl acetate (0.517 g, 3.35
mmol, 1 equiv, prepared in 4 steps following a known procedure)21 was dissolved in
DCM/tBuOH (5:1, 33 mL) and sodium bicarbonate (2.17 g, 25.92 mmol, 4 equiv) was added.
The suspension was cooled to -78 °C forming a slurry through which ozone was bubbled for 2 h
until starting material was no longer present by TLC. The cold bath was dropped and the reaction
was purged with nitrogen. Acetic anhydride (1.84 mL, 19.4 mmol, 3 equiv) and triethylamine
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(1.36 mL, 9.72 mmol, 1.5 equiv) were added to the reaction via syringe and and the reaction was
stirred overnight at room temperature. The reaction was filtered over celite then washed with 0.1
M HCl, saturated sodium bicarbonate, brine, dried over MgSO4, filtered, and concentrated under
reduced pressure to provide a dark red oil. The oil was purified via flash chromatography (4:1
hexanes/EA) to provide 1n (0.634 g, 38%) as a light yellow oil. Rf = 0.18 (4:1 hexanes/EA); 1H
NMR (500 MHz, CDCl3) δ 5.01 (dd, J = 8.2, 4.2 Hz, 1H), 2.27 (td, J = 7.2, 1.7 Hz, 2H), 2.18 (s,
3H), 2.17 (s, 3H), 1.89 – 1.63 (m, 4H), 1.46 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 205.0, 172.3,
170.5, 80.5, 78.3, 34.8, 29.5, 28.1, 26.1, 20.7, 20.7; IR (thin film): C=O, 1729 cm-1; HRMS
(TOF-ESI) m/z calc’d for C13H22LiO5 [M+ H]+, 265.1628; found, 265.1625.
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tert-Butyl 2-(2-Chlorophenyl)pent-4-enoate (1o). Under a nitrogen atmosphere,
diisopropylamine (2.06 mL, 14.68 mmol, 1.05 equiv) was dissolved in THF (140 mL) and
cooled to -78 °C. n-BuLi (10.23 mL of 1.44 M, 1.1 equiv) was added and the reaction was
warmed to 0 °C and stirred for 30 min. The reaction was cooled to -78 °C and compound 1k (3.17
g, 13.98 mmol in 5 mL) was added via cannula and reaction was stirred at -78 oC for 1 h. The
reaction turned bright yellow in color. Allyl bromide (1.27 mL, 14.68 mmol, 1.05 equiv) was
added to the reaction dropwise over 10 minutes. The reaction was warmed to room temperature
and stirred overnight. The reaction was concentrated under reduced pressure then redissolved in
hexanes/EA (5:1), washed with sat. NH4Cl (2x), brine, dried over MgSO4, filtered, and
concentrated under reduced pressure to provide a deep red oil. The crude material was purified
via flash chromatography (50:1 hexanes/EA) to provide 1o (3.412g, 92%) as a colorless oil. Rf =
0.60 (10:1 hexanes/EA) 1H NMR (400 MHz, CDCl3) δ 7.358 (dd, J = 7.7, 1.8 Hz, 1H), 7.353
(dd, J = 7.7, 1.5 Hz, 1H), 7.22 (td, J = 7.5, 1.6 Hz, 1H), 7.16 (td, J = 7.6, 1.8 Hz, 1H), 5.80-5.69
(m, 1H), 5.11 – 4.93 (m, 2H), 4.11 (dd, J = 8.3, 6.8 Hz, 1H), 2.78 – 2.69 (m, 1H), 2.53-2.43 (m,
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1H), 1.39 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 172.0, 137.0, 135.2, 134.0, 129.6, 128.5, 128.1,
126.9, 116.8, 81.0, 48.1, 36.7, 27.9; IR (thin film): C=O, 1729 cm-1; HRMS (ESI-TOF) m/z
calc’d for C15ClH19O2 [M+ Li]+, 272.1225; found, 272.1217.
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tert-Butyl 2-(2-Chlorophenyl)-4-hydroxybutanoate (1t). Compound 1o (4.81 g, 18.0 mmol) was
dissolved in MeOH (180 mL) and cooled to -78 °C. Ozone was bubbled through for 30 minutes
until the appearance of a light blue color. Oxygen was bubbled through until the blue color
dissipated, then dimethyl sulfide (1.73 mL, 23.4 mmol, 1.3 equiv) was added to the reaction. The
reaction was warmed to room temperature and stirred overnight under a nitrogen atmosphere.
The reaction was concentrated under reduced pressure to provide a pale yellow residue which
was subsequently purified via flash chromatography (10:1 hexanes/EA) to provide the
corresponding aldehyde (3.62 g, 75%) as a clear oil. Rf = 0.36 (10:1 hexanes/EA); 1H NMR (400
MHz, CDCl3) δ 9.79 (X of ABMX; broad s, 1H), 7.40 – 7.36 (m, 1H), 7.26 – 7.17 (m, 3H), 4.55
(M of ABMX, J = 9.6, 4.5 Hz, 1H), 3.25 (B of ABMX, J = 18.3, 9.6, 1.0 Hz, 1H), 2.74 (A of
ABMX, J = 18.3, 4.6, 0.7 Hz, 1H), 1.41 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 199.4, 171.2,
136.4, 133.6, 129.9, 128.7, 128.5, 127.2, 81.7, 45.9, 43.1, 27.8; IR thin film: C=O, 1726 cm-1;
HRMS (ESI-TOF) m/z calc’d for C14H17ClO3 [M+ Li]+, 275.1027; found, 275.1016.
The aldehyde obtained from the above procedure (2.288 g, 8.513 mmol) was dissolved in tert-
butanol (85 mL) and the flask was purged with nitrogen. Sodium borohydride (0.644 g, 17.02
mmol, 2 equiv) was added to the reaction and was stirred for 15 min until starting material was
no longer present by TLC. The reaction was quenched by the addition of water and extracted
with ethyl acetate (2x). The organic layers were combined, washed with brine, dried over
MgSO4, filtered, and concentrated under reduced pressure to provide a crude colorless oil. The
crude residue was purified via flash chromatography (5:1 hexanes/EA) to provide 1t (2.02 g,
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88%) as a clear oil. Rf = 0.23 (5:1 hexanes/EA) 1H NMR (500 MHz, CDCl3) δ 7.38 (dd, J = 7.8,
1.4 Hz, 1H), 7.34 (dd, J = 7.7, 1.9 Hz, 1H), 7.24 (td, J = 7.4, 1.3 Hz, 1H), 7.21 – 7.16 (m, 1H),
4.22 (X of ABNMX, apparent t, J = 7.3 Hz), 3.76-3.55 (M and N of ABMNX, m, 2H), 2.39 –
2.26 (B of ABMNX, m, 1H), 2.01 – 1.91 (A of ABMNX, m, 1H), 1.76 (s, 1H), 1.40 (s, 9H); 13C
NMR (101 MHz, CDCl3) δ 172.8, 137.2, 133.9, 129.7, 128.7, 128.2, 127.0, 81.2, 60.7, 45.6,
35.2, 27.9; IR (thin film): OH, 3449, C=O, 1727cm-1; HRMS (ESI-TOF) m/z calc’d for
C14H19ClO3 [M+ Li]+, 277.1183; found, 277.1182.
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tert-Butyl 2-(2-Chlorophenyl)-4-(tosyloxy)butanoate (1p). Alcohol 1t (0.315 g, 1.16 mmol) was
dissolved in anhydrous pyridine (12 mL) and p-toluenesulfonyl chloride (0.443 g, 2.32 mmol, 2
equiv) was added. The flask was purged with nitrogen and stirred at room temperature overnight.
The reaction was quenched with the addition of water (100 mL) and subsequently extracted with
hexanes/EA (5:1, 2x). The combined organic layers were washed with water (2x), brine, dried
over MgSO4, filtered, and concentrated under reduced pressure to provide a crude colorless oil.
The crude material was purified via flash chromatography (10:1 hexanes/EA) to provide 1p
(0.305 g, 62%) as a colorless oil. Rf = 0.20 (10:1 hexanes/EA); 1H NMR (400 MHz, CDCl3) δ
7.74 (d, J = 8.2 Hz, 2H), 7.35 – 7.28 (m, 3H), 7.20 – 7.13 (m, 3H), 4.13 – 4.02 (X and N of
ABMNX, m, 2H), 3.92 (M of ABMNX, J = 9.9, 7.1, 5.6 Hz, 1H), 2.45 – 2.32 (B of ABMNX, m,
4H), 2.10 – 1.96 (A of ABMNX, m, 1H), 1.34 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 171.5,
144.9, 136.3, 134.1, 133.0, 130.0, 130.0, 128.9, 128.6, 128.0, 127.2, 81.6, 68.2, 45.0, 31.3, 28.0,
21.8; IR (thin film): C=O, 1726 cm-1; HRMS (ESI-TOF) m/z calc’d for C21H25ClO5S [M+ Li]+,
431.1272; found, 431.1268.
tert-Butyl 4-(Benzyloxycarbonyloxy)-2-(2-chlorophenyl)butanoate (1q). Under a nitrogen
atmosphere, alcohol 1t (0.224 g, 0.83 mmol, 1 equiv) and DMAP (0.009 g, 0.083 mmol, 0.1
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equiv), were dissolved in DCM (8 mL). Triethylamine (0.115 mL, 0.83 mmol, 1 equiv) was then
added via syringe, and cooled to 0 °C. Benzylchloroformate (0.236 mL, 1.06 mmol, 2 equiv) was
then added to the reaction dropwise via syringe over 15 minutes. The reaction was warmed to
room temperature and was stirred for 16 h. The reaction was diluted with hexanes/EA (1:1, 15
mL), washed with water (2x 10 mL), brine, dried over MgSO4, filtered and concentrated to
provide a crude colorless oil. The crude residue was purified via flash chromatography (20:1
hexanes/EA) to provide 1q (0.080g, 24%) as a colorless oil. Rf = 0.20 (20:1 hexanes/EA); 1H
NMR (500 MHz, CDCl3) δ 7.47 – 7.32 (m, 6H), 7.30 (dd, J = 7.6, 1.9 Hz, 1H), 7.22 (td, J = 7.5,
1.7 Hz, 1H), 7.19 (td, J = 7.5, 1.9 Hz, 1H), 5.15 (s, 2H), 4.22 – 4.09 (M, N, and X of ABMNX,
m, 3H), 2.44 (B of ABMNX, J = 13.6, 7.3, 6.1 Hz, 1H), 2.09 (A of ABMNX, J = 13.7, 7.4, 6.2
Hz, 1H), 1.39 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 171.9, 155.1, 136.7, 135.3, 134.1, 129.9,
128.7, 128.7, 128.6, 128.5, 128.4, 127.2, 81.4, 77.2, 69.7, 65.9, 45.2, 31.4, 28.0; IR (thin film):
C=O, 1747, 1728 cm-1; HRMS (ESI-TOF) m/z calc’d for C22H25ClO5 [M+Li]+, 410.1542; found,
410.1535.
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tert-Butyl 4 (((9H-fluoren-9-yl) methoxy)carbonyloxy)-2-(2-chlorophenyl)butanoate (1r). Under
a nitrogen atmosphere, alcohol 1t (0.272 g, 1.00 mmol) dissolved in pyridine (5 mL) was added
dropwise via cannula to 9-fluorenylmethoxycarbonyl (Fmoc) chloride (0.312 g, 1.20 mmol, 1.2
equiv) dissolved in pyridine (5 mL). The reaction was stirred at room temperature overnight.
Water (15 mL) was added to quench the reaction and was subsequently extracted with EA (2x).
The combined organic layers were washed with brine (2x), dried over MgSO4, filtered, and
concentrated under reduced pressure to provide a brown oil. The crude residue was purified via
flash chromatography (20:1 hexanes/EA) to provide 1r (0.180 g, 37%) as a colorless oil. Rf =
0.20 (10:1 hexanes/EA); 1H NMR (500 MHz, CDCl3) δ 7.78 (d, J = 7.8 Hz, 2H), 7.63 (d, J = 7.5
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Hz, 2H), 7.46 – 7.36 (m, 3H), 7.37 – 7.30 (m, 3H), 7.26 – 7.14 (m, 2H), 4.39 (d, J = 7.8 Hz, 2H),
4.30 – 4.17 (X and N of ABMNX, m, 2H), 4.13 (M of ABMNX, J = 10.8, 7.2, 6.0 Hz, 1H), 2.48
(B of ABMNX, J = 13.6, 7.3, 6.1 Hz, 1H), 2.13 (A of ABMNX, J = 13.8, 7.5, 6.2 Hz, 1H), 1.41
(s, 9H); 13C NMR (101 MHz, CDCl3) δ 171.9, 155.2, 143.5, 143.5, 141.4, 136.8, 134.2, 130.0,
128.7, 128.6, 128.0, 127.3, 127.3, 125.3, 125.3, 120.2, 81.5, 69.9, 66.0, 46.9, 45.2, 31.5, 28.0; IR
(thin film): C=O, 1747, 1728 cm-1; HRMS (ESI-TOF) m/z calc’d for C29H29ClO5 [M+Li]+,
499.1864; found, 499.1862.
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tert-Butyl 2-(2-Chlorophenyl)-4-(pivaloyloxy)butanoate (1s). Under a nitrogen atmosphere,
alcohol 1t (0.265 g, 0.979 mmol, 1 equiv) and DMAP (0.002 g, 0.019 mmol, 0.2equiv) were
dissolved in DCM (10 mL). Triethylamine (0.177 mL, 1.27 mmol, 1.3 equiv) was added via
syringe, and the reaction was cooled to 0 °C. Trimethylacetyl chloride (0.145 mL, 0.117 mmol,
1.2 equiv) was added dropwise via syringe to the reaction over 10 minutes. The reaction was
warmed to room temperature and stirred for 16 h. The reaction was diluted with hexanes/EA
(1:1, 15 mL), washed with water (2x), brine, dried over MgSO4, filtered, and concentrated under
reduced pressure to provide a yellow oil. The crude material was purified via flash
chromatography (20:1 hexanes/EA) to provide 1m (0.262 g, 76%) as a colorless oil. Rf = 0.52
(10:1 hexanes/EA); 1H NMR (500 MHz, CDCl3) δ 7.37 (dd, J = 7.9, 1.5 Hz, 1H), 7.33 (dd, J =
7.7, 1.8 Hz, 1H), 7.24 (td, J = 7.5, 1.5 Hz, 1H), 7.19 (td, J = 7.6, 1.8 Hz, 1H), 4.20 (X of
ABMNX apparent t, J = 7.5 Hz, 1H), 4.08 (N of ABMNX, J = 11.1, 7.3, 5.7 Hz, 1H), 3.99 (M of
ABMNX, J = 11.1, 6.2 Hz, 1H), 2.40 – 2.30 (B of ABMNX, m, 1H), 2.07 (A of ABMNX, J =
14.3, 7.3, 5.9 Hz, 1H), 1.40 (s, 9H), 1.20 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 178.6, 172.1,
136.9, 134.2, 129.9, 128.7, 128.5, 127.3, 81.4, 62.2, 45.2, 38.9, 31.6, 28.0, 27.3; IR (thin film):
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C=O, 1729 cm-1; HRMS (ESI-TOF) m/z calc’d for C19H27ClO4 [M+Li]+, 360.1749; found,
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tert-Butyl 2-(2-Chlorophenyl)-4-triethylsilyloxy)butanoate (1u). Alcohol 1t (0.197 g, 0.727
mmol) was dissolved in DCM (7 mL) and cooled to 0 °C under a nitrogen atmosphere.
Triethylamine (0.202 mL, 1.45 mmol, 2 equiv) then triethylsilyl trifluoromethanesulfonate
(TESOTf) (0.164 mL, 0.272 mmol, 1 equiv) were added to the reaction dropwise via syringe.
The reaction was stirred at 0 °C for 1 h until starting material could no longer be observed by
TLC. The reaction was diluted with hexanes/EA (1:1), washed with NaHCO3 (sat.), water, brine,
dried over MgSO4, filtered, and concentrated under reduced pressure to provide a light pink oil.
The crude residue was purified via flash chromatography (10:1 hexanes/EA) to provide 1u
(0.197 g, 70%) as a colorless oil. Rf = 0.48 (10:1 hexanes/EA); 1H NMR (400 MHz, CDCl3) δ
7.36 (dd, J = 7.8, 1.6 Hz, 1H), 7.33 (dd, J = 7.6, 1.9 Hz, 1H), 7.22 (td, J = 7.5, 1.6 Hz, 1H), 7.17
(td, J = 7.5, 1.9 Hz, 1H), 4.22 (X of ABMNX, J = 8.0, 6.8 Hz, 1H), 3.68 – 3.52 (M and N, of
ABMNX, m, 2H), 2.29 (B of ABMNX, J = 12.8, 8.0, 6.3 Hz, 1H), 1.94 (A of ABMNX, J = 13.4,
6.6 Hz, 1H), 1.39 (s, 9H), 0.94 (t, J = 8.0 Hz, 9H), 0.57 (q, J = 7.8 Hz, 6H); 13C NMR (101 MHz,
CDCl3) δ 173.0, 137.9, 134.5, 130.1, 129.2, 128.4, 127.3, 81.3, 60.9, 45.4, 35.8, 28.4, 7.2, 4.8; IR
(thin film): C=O,1729 cm-1; HRMS (ESI-TOF) m/z calc’d for C20H33ClO3Si [M+Li]+, 391.2048;
found, 391.2047.
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tert-Butyl 4-(tert-Butyldimethylsilyloxy)-2-(2-chlorophenyl)butanoate (1v). Alcohol 1t (0.478 g,
1.76 mmol) was dissolved in THF (18 mL), imidazole (0.359 g, 5.28 mmol, 3 equiv) was added,
and the flask was purged with nitrogen. tert-Butyldimethylsilylchloride (TBDMSCl) (0.346 g,
2.3 mmol, 1.3 equiv, in 2 mL of THF) was then added via cannula and the reaction was stirred at
room temperature. After a few seconds a white precipitate formed in the reaction. After 30
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minutes the reaction was found to be complete by TLC. The reaction was diluted with
hexanes/EA (1:1) washed with water (2x), brine, dried over MgSO4, filtered, and concentrated to
provide a colorless oil. The crude product was purified via flash chromatography to provide 1v
(0.450 g, 66%) as a colorless oil. Rf = 0.31 (10:1 hexanes/EA); 1H NMR (500 MHz, CDCl3) δ
7.38 (dd, J = 7.9, 1.5 Hz, 1H), 7.35 (dd, J = 7.7, 1.8 Hz, 1H), 7.23 (td, J = 7.5, 1.5 Hz, 1H), 7.19
(td, J = 7.6, 1.8 Hz, 1H), 4.26 (X of ABMNX, J = 8.1, 6.7 Hz, 1H), 3.66 – 3.55 (M and N of
ABMNX, m, 2H), 2.27 (B of ABMNX, J = 14.0, 8.0, 6.0 Hz, 1H), 1.94 (A of ABMNX, J = 13.4,
6.6 Hz, 1H), 1.41 (s, 9H), 0.90 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H); 13C NMR (101 MHz, CDCl3) δ
172.5, 137.5, 134.0, 129.6, 128.8, 127.9, 126.8, 80.8, 60.6, 44.8, 35.3, 27.9, 25.9, 18.2, -5.4, -5.5;
IR (thin film): C=O, 1729 cm-1; HRMS (ESI-TOF) m/z calc’d for C20H33ClO3Si [M+ Li]+,
391.2048; found 391.2043.
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tert-Butyl 2-(2-Chlorophenyl)-4-(triisopropylsilyloxy)butanoate (1w). Alcohol 1t (0.336 g,
1.24mmol) was dissolved in THF (12 mL) at room temperature, imidazole (0.253 g, 3.72 mmol,
3 equiv) was added, and the flask was purged with nitrogen. Triisopropylsilyl chloride (TIPSCl)
(0.345 mL, 1.61 mmol, 1.3 equiv) was added to the solution dropwise via syringe. A white
precipitate was observed and the reaction was stirred overnight at room temperature until starting
material was no longer present by TLC. The reaction was diluted with hexanes/EA (1:1) and
subsequently washed with water (2x), brine, dried over MgSO4, filtered, and concentrated under
reduced pressure to provide a colorless oil. The crude product was purified via flash
chromatography (20:1 hexanes/EA) to provide 1w (0.280g, 53%) as a colorless oil. 1H NMR
(500 MHz, CDCl3) δ 7.36 (dd, J = 6.2, 1.3 Hz, 1H), 7.34 (dd, J = 6.4, 1.2 Hz, 1H), 7.22 (td, J =
7.5, 1.5 Hz, 1H), 7.16 (td, J = 7.6, 1.8 Hz, 1H), 4.31 (X of ABMNX, J = 8.3, 6.4 Hz, 1H), 3.69
(M and N of ABMNX, m, Hz, 2H), 2.27 (B of ABMNX, J = 14.0, 8.3, 5.8 Hz, 1H), 1.94 (A of
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ABMNX, J = 13.4, 6.6 Hz, 1H), 1.39 (s, 9H), 1.12 – 0.97 (m, 21H); 13C NMR (101 MHz,
CDCl3) δ 172.6, 137.6, 134.0, 129.6, 128.8, 127.9, 126.8, 80.7, 60.9, 44.8, 35.5, 27.9, 18.0, 11.9;
IR (thin film): C=O, 1729 cm-1; HRMS (ESI-TOF) m/z calc’d for C23H39ClO3Si [M+ Li]+,
433.2517; found 433.2517.
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tert-Butyl 4-(Benzyloxy)-2-(2-chlorophenyl)butanoate (1x). Under a nitrogen atmosphere,
alcohol 1t (0.286 g, 1.06 mmol, 1 equiv) was dissolved in 1,4-dioxane (10 mL). Benzyl 2,2,2-
trichloroacetimidate (0.392 mL, 0.212 mmol, 2 equiv) and triflic acid (0.019 mL, 0.212 mmol,
0.2 equiv) were added to the reaction via syringe and stirred at room temperature for 16 h.
Reaction was diluted with hexanes/EA (1:1), and the organic layer was washed with NaHCO3
sat. (2x), brine, dried over MgSO4, filtered, and concentrated to provide a tan solid. The crude
product was purified via flash chromatography (50:1 hexanes/EA) to provide 1x (0.118 g, 31%)
as a colorless oil. Rf = 0.21 (50:1 hexanes/EA); 1H NMR (500 MHz, CDCl3) δ 7.37 (dd, J = 7.8,
1.6 Hz, 1H), 7.35 – 7.31 (m, 5H), 7.29-7.27 (m, 1H), 7.22 (td, J = 7.5, 1.6 Hz, 1H), 7.18 (td, J =
7.6, 1.9 Hz, 1H), 4.48 (B of AB, J = 11.9 Hz, 1H), 4.45 (A of AB, J = 11.9 Hz, 1H), 4.26 (X of
ABMNX, apparent t, J = 7.4 Hz, 1H), 3.50 (N of ABMNX, J = 9.5, 6.0 Hz, 1H), 3.39 (M of
ABMNX, J = 9.5, 7.3, 5.8 Hz, 1H), 2.40 (B of ABMNX, J = 13.5, 7.4, 6.0 Hz, 1H), 2.04 (A of
ABMNX, J = 13.6, 7.5, 5.9 Hz, 1H), 1.38 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 172.5, 138.5,
137.4, 134.2, 129.8, 129.0, 128.5, 128.2, 127.8, 127.7, 127.1, 81.0, 73.1, 67.9, 45.6, 32.5, 28.0;
IR (thin film): C=O, 1726 cm-1; HRMS (ESI-TOF) m/z calc’d for C21H25ClO3 [M+Li]+,
367.1653; found, 367.1654.
General Procedure for the synthesis of acid chlorides: The tert-butyl ester (1 mmol; 1 equiv)
was dissolved in SOCl2 (0.70 mL; 10 mmol; 10 equiv) in a 2 dram (7.4 mL) vial equipped with a
magnetic stir bar at room temperature. Water (18 µl; 1mmol; 1 equiv) was then added and the
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vial was capped with a teflon-lined cap. Note that the vial was never filled more than 40% full to
avoid the possibility of rupture! The reaction was stirred, at which point, gas evolution was
observed. Stirring was continued for the length of time indicated in Table 5. The cap was then
carefully removed (Caution: contents under pressure!), and toluene (1 mL) was added to the vial
and removed at reduced pressure to effect azeotropic removal of SOCl2 and provide the product.
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Large scale acid chloride synthesis open to atmosphere: 3-Phenylpropanoyl Chloride (2a)
The tert-butyl dihydrocinnamate (4.174 g, 20.2 mmol, 1 equiv) was dissolved in SOCl2 (20
equiv, 28.5 mL) equipped with a magnetic stir bar at room temperature. Concd HCl (1 equiv,
1.66 mL) was then added and the flask was subsequently capped with a polyethylene cap that
was punctured with a 21g needle for a vent to the atmosphere. The reaction was stirred, at which
point, gas evolution was observed, and stirring continued for 16 h at room temperature. Toluene
(5 ml x2) was added to the flask and removed at reduced pressure to effect azeotropic removal of
SOCl2. The crude material was isolated in a 98% yield. The crude material was then subjected to
vacuum distillation to isolate product as a clear oil (3.102g, 91% yield).
3-Phenylpropanoyl Chloride (2a). This compound was prepared according to the general
procedure to provide 2a (0.101 g, 91%) as a colorless oil. 1H and 13C NMR are in accord with
those reported in the literature.22
Benzoyl Chloride (2b). This compound was prepared according to the general procedure with an
extended reaction time of 5 h to provide 2b as a colorless oil (0.110 g, 90%). 1H and 13C NMR
are in accord with those reported in the literature.23
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2-Fluorobenzoyl Chloride (2c) This compound was prepared according to the general procedure
with an extended reaction time of 5 h to provide 2c as a pale yellow oil (0.046 g, 92%). 1H and
13C NMR are in accord with those reported in the literature.24
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4-Fluorobenzoyl Chloride (2d) This compound was prepared according to general procedure
with an extended reaction time of 16 h to provide 2d as a pale yellow oil (0.062 g, 90%). 1H and
13C NMR are in accord with those reported in the literature.25
2-Bromobenzoyl Chloride (2e). This compound was prepared according to the general procedure
to provide 2e (0.044 g, 95%) as a colorless oil.26
3,5-Dimethoxybenzoyl Chloride (2f). This compound was prepared according to the general
procedure with extended reaction time to 16 h to provide 2f (0.080 g, 94%). 1H and 13C NMR are
in accord with those reported in the literature.27
4-(Chlorocarbonyl)phenyl Acetate (2g). This compound was prepared according to the general
procedure with extended reaction time to 16 h to provide 2g (0.054, 89%). 1H NMR (500 MHz,
CDCl3) δ 8.18 (d, J = 8.8 Hz, 2H), 7.28 (d, J = 8.8 Hz, 2H), 2.36 (s, 3H). 13C NMR (101 MHz,
CDCl3) δ 168.6, 167.5, 156.2, 133.2, 130.7, 122.4, 21.3. IR (thin film): C=O, 1774 cm-1; HRMS
(ESI-TOF) m/z calc’d for C9H7O3 [M-Cl]+, 163.0395; found, 163.0413.
2-Benzoylbenzoyl Chloride (2h) This compound was prepared according to the general procedure
with extended reaction time to 16 h to provide 2h 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 7.6
Hz, 1H), 7.79 (apparent t, J = 7.5 Hz, 1H), 7.74 – 7.68 (m, 3H), 7.64 (apparent t, J = 7.4 Hz, 1H),
7.46 – 7.41 (m, 3H). 13C NMR (101 MHz, CDCl3) δ 167.1, 151.3, 138.2, 135.5, 130.9, 130.0,
128.8, 126.0, 125.9, 123.6, 123.5, 110.1, 99.9. IR (thin film): C=O, 1791 cm-1; HRMS (ESI-
TOF) m/z calc’d for C14H9O2Cl [M+Li]+, 251.0451; found, 251.0442.
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4-Nitrobenzoyl Chloride (2i) This compound was prepared according to the general procedure
with extended reaction time to 16 h and run in toluene (0.1 M), heated to 100 °C to provide 2i
(0.080 g, 94%) 1H and 13C NMR are in accord with those reported in the literature.28
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4-Acetylbenzoyl Chloride (2j) This compound was prepared according to the general procedure
with extended reaction time to 16 h and run in toluene (0.1 M) heated to 100 °C to provide 2j
(0.054 g, 93%). 1H NMR (400 MHz, CDCl3) δ 8.25 – 8.21 (m, 2H), 8.10 – 8.06 (m, 2H), 2.69 (s,
3H); 13C NMR (101 MHz, CDCl3) δ 197.1, 168.0, 141.8, 136.6, 131.7, 128.7, 27.2; IR (thin
film): C=O, 1773, 1736, 1687 cm-1; HRMS (ESI-TOF) m/z calc’d for C9H7O2 [M-Cl]+,
147.0446; found, 147.0451.
2-(2-Chlorophenyl)acetyl Chloride. (2k). This compound was prepared according to the general
procedure to provide 2k (0.072 g, 90%). 1H NMR (400 MHz, CDCl3) δ 7.44 – 7.38 (m, 1H), 7.32
– 7.23 (m, 3H), 4.28 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 170.8, 134.7, 131.6, 130.2, 129.9,
129.8, 127.2, 50.8; IR (thin film): C=O, 1798 cm-1. HRMS (ESI-TOF) m/z calc’d for C8H6OCl
[M-Cl]+, 153.0107; found 153.0104 (minor component).
2,2-Diphenylacetyl Chloride (2l). This compound was prepared according to the general
procedure to provide 2l as an off-white amorphous solid (0.064 g, 91%). 1H and 13C NMR are in
accord with those reported in the literature.29
(R)-2-(1,3-Dioxoisoindolin-2-yl)-3-methylbutanoyl Chloride (2m). This compound was prepared
according to the general procedure to provide 2m as a white solid (0.070 g, 95%). Mp = 117-119
°C. 1H NMR (500 MHz, CDCl3) δ 7.95 (dd, J = 5.5, 3.1 Hz, 2H), 7.82 (dd, J = 5.5, 3.0 Hz, 2H),
4.76 (d, J = 8.4 Hz, 1H), 2.77 (dhept, J = 8.5, 6.8 Hz, 1H), 1.18 (d, J = 6.6 Hz, 3H), 0.93 (d, J =
6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 170.0, 167.1, 134.8, 131.5, 124.1, 77.2, 66.5, 29.3,
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20.5, 19.2. IR (thin film): C=O, 1805, 1784, 1723 cm-1; [α] = 101.6°; HRMS (TOF-ESI) m/z
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calc’d for C9ClH13NO4 [M-Cl]+, 230.0817; found, 230.0811.
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(R)-methyl 2-(1,3-dioxoisoindolin-2-yl)-3-methylbutanoate (3m). Compound 2m (0.026 g, 0.098
mmol,1 equiv) dissolved in DCM (0.5 mL), was added via cannula to a solution of MeOH (.040
mL, 0.98mmol, 10 equiv), Hunigs base (0.025 mL, 1.5 equiv) in DCM (0.1 M). The reaction was
left to stir for 1h until there was no change by TLC. Reaction was diluted with 1:1
hexanes:EtOAc then subsequently washed with sat. sodium bicarbonate (2x), brine, dried of over
MgSO4, filtered, and concentrated to obtain crude material as a colorless oil. The crude product
was purified via flash chromatography (10:1 hexanes/EA) to provide 3m as a colorless oil
(0.022g, 85% yield). 1H and 13C NMR are in accord with those reported in the literature.30
7-Chloro-2,7-dioxoheptan-3-yl Acetate (2n). This compound was prepared according to the
general procedure to provide 2n (0.093 g, 95%) as a brown oil. 1H NMR (500 MHz, CDCl3) δ
5.02 (m, J = 7.5, 4.0 Hz, 1H), 2.97 (t, J = 6.8 Hz, 2H), 2.19 (s, 3H), 2.18 (s, 3H), 1.93 – 1.76 (m,
4H); 13C NMR (101 MHz, CDCl3) δ 204.6, 173.3, 170.4, 77.7, 46.3, 28.6, 26.1, 20.7, 20.6; IR
(thin film): C=O, 1799, 1759, 1729 cm-1; HRMS (TOF-ESI) m/z calc’d for C9ClH13O4 [M+ Li]+,
227.0663; found, 227.0663.
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2-(2-Chlorophenyl)pent-4-enoyl Chloride (2o). This compound was prepared according to the
general procedure to provide 2o (0.082 g, 98%) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.46
– 7.40 (m, 1H), 7.32 – 7.22 (m, 3H), 5.70 (ddt, J = 17.0, 10.2, 6.9 Hz, 1H), 5.12 – 5.03 (m, 2H),
4.66 (apparent t, J = 7.4 Hz, 1H), 2.92 – 2.84 (m, 1H), 2.62 – 2.53 (m, 1H); 13C NMR (101 MHz,
CDCl3) δ 173.7, 134.4, 133.7, 133.1, 130.1, 129.5, 129.0, 127.4, 118.5, 59.0, 36.6; IR (thin film):
C=O 1793 cm-1; HRMS (ESI-TOF) m/z calc’d for C11Cl2H10O [M+ Li]+, 234.0260; found,
234.0265.
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4-Chloro-3-(2-chlorophenyl)-4-oxobutyl 4-Methylbenzenesulfonate (2p). This compound was
prepared according to the general procedure with extended reaction time to 5 h to provide 2p
(0.042 g, 91%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 8.0 Hz, 2H), 7.42 –
7.37 (m, 1H), 7.32 (d, J = 8.1 Hz, 2H), 7.30-7.22 (m, 2H), 7.16 – 7.11 (m, 1H), 4.60 (X of
ABMNX, J = 7.8, 6.7 Hz, 1H), 4.06 (N of ABMNX, J = 10.3, 6.4, 5.0 Hz, 1H), 3.88 (M of
ABMNX, J = 10.3, 7.7, 4.7 Hz, 1H), 2.51 (B of ABMNX, J = 14.7, 7.8, 6.8, 5.0 Hz, 1H), 2.43 (s,
3H), 2.15 (A of ABMNX, J = 14.5, 7.9, 6.4, 4.7 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 173.9,
145.2, 134.4, 133.1, 132.6, 130.6, 130.1, 130.0, 129.7, 128.0, 127.8, 66.8, 55.8, 31.4, 21.8; IR
(thin film): C=O, 1796 cm-1; HRMS (ESI-TOF) m/z calc’d for C17H16Cl2O4S [M+ Li]+,
393.0307; found, 393.0323.
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Benzyl 4-Chloro-3-(2-chlorophenyl)-4-oxobutylcarbonate (2q). This compound was prepared
according to the general procedure with extended reaction time to 16 h to provide 2q (0.009 g
91%) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.44 (dt, J = 6.0, 3.4 Hz, 1H), 7.40 – 7.33
(m, 5H), 7.32 – 7.27 (m, 2H), 7.25 – 7.21 (m, 1H), 5.16 (s, 2H), 4.72 (X of ABMNX, J = 8.2, 6.4
Hz, 1H), 4.17 (N of ABMNX, J = 11.4, 5.7 Hz, 1H), 4.02 (M of ABMNX, J = 11.1, 8.0, 5.1 Hz,
1H), 2.57 (B of ABMNX, J = 14.5, 7.9, 6.5, 5.5 Hz, 1H), 2.19 (A of ABMNX, J = 14.4, 8.2, 6.0,
5.1 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 174.1, 154.9, 135.2, 134.6, 133.5, 130.6, 130.0,
129.4, 128.8, 128.5, 127.9, 77.2, 69.9, 64.7, 56.1, 31.5; IR (thin film): C=O, 1794, 1747 cm-1;
HRMS (ESI-TOF) m/z calc’d for C18H16Cl2O4 [M+Li]+, 372.0577; found, 372.0576.
(9H-fluoren-9-yl)methyl 4-Chloro-3-(2-chlorophenyl)-4-oxobutanylcarbonate (2r). This
compound was prepared according to the general procedure to provide 2r (0.016 g, 94%) as a
colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.78 (dt, J = 7.5, 0.9 Hz, 2H), 7.62 (ddd, J = 7.5, 2.2,
1.0 Hz, 2H), 7.49 – 7.45 (m, 1H), 7.43 – 7.40 (m, 2H), 7.37 – 7.29 (m, 4H), 7.27 – 7.23 (m, 1H),
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4.77 (X of ABMNX, J = 8.2, 6.5 Hz, 1H), 4.42 (B of AB, J = 1.6 Hz, 1H), 4.40 (A of AB, J =
1.0 Hz, 1H), 4.20 (N of ABMNX, J = 11.3, 5.7 Hz, 1H), 4.05 (M of ABMNX, J = 11.1, 8.0, 5.1
Hz, 1H), 2.61 (B of ABMNX, J = 14.6, 8.1, 6.5, 5.4 Hz, 1H), 2.22 (A of ABMNX, J = 14.4, 8.2,
6.0, 5.0 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 174.1, 155.0, 143.4, 143.4, 141.4, 134.7, 133.5,
130.6, 130.0, 129.3, 128.1, 127.9, 127.3, 127.3, 125.3, 125.3, 120.2, 70.1, 64.8, 56.1, 46.9, 31.5;
IR (thin film): C=O, 1791 cm-1; HRMS (ESI-TOF) m/z calc’d for C25H20Cl2O4 [M+Li]+,
461.0899; found, 461.0902.
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4-Chloro-3-(2-chlorophenyl)-4-oxobutyl pivalate (2s). This compound was prepared according
to the general procedure to provide 2s (0.036 g, 95%) as a colorless oil. 1H NMR (500 MHz,
CDCl3) δ 7.52 – 7.44 (m, 1H), 7.35 – 7.27 (m, 3H), 4.76 (X of ABMNX, J = 7.1 Hz, 1H), 4.14
(bs, 1H), 4.00 (bs, 1H), 2.54 (bs, 1H), 2.17 (bs, 1H), 1.23 (s, 9H); 13C NMR (101 MHz, CDCl3) δ
178.5, 174.1, 134.5, 133.6, 130.5, 129.9, 129.1, 127.8, 61.4, 56.3, 38.9, 31.8, 27.3; IR (thin film):
C=O 1793, 1729 cm-1. HRMS (ESI-TOF) m/z calc’d for C15H18ClO3 [M-Cl]+, 281.0945; found,
281.0934.
3-(2-Chlorophenyl)dihydrofuran-2(3H)-one (8). This compound was prepared according to the
general procedure with extended reaction time to 16 h to provide 8 as a colorless oil, (84-98%),
1H NMR (500 MHz, CDCl3) δ 7.43 (dt, J = 7.3, 1.2 Hz, 1H), 7.35 – 7.22 (m, 3H), 4.52 (N of
ABMNX, J = 8.8, 2.9 Hz, 1H), 4.40 (M of ABMNX, J = 9.4, 6.7 Hz, 1H), 4.25 (X of ABMNX,
J = 10.7, 9.2 Hz, 1H), 2.87 – 2.73 (B of ABMNX, m, 1H), 2.38 (A of ABMNX, J = 12.8, 10.7,
9.7, 8.5 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 176.8, 135.0, 134.2, 130.1, 129.6, 129.2, 127.6,
66.7, 44.0, 31.0; IR (thin film): C=O, 1771 cm-1; HRMS (ESI-TOF) m/z calc’d for C10H9ClO2
[M+Li]+, 203.0451; found, 203.0453.
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ASSOCIATED CONTENT
Supporting Information
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Copies of 1H and 13C NMR spectra of products for the reactions described in Tables 3 and 4 are
provided. The material is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: Sammakia@colorado.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the National Science Foundation under grant CHE 1266167 and is
based upon work supported by a National Science Foundation Graduate Research Fellowship
award to JG under grant DGE 1144083.
REFERENCES
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(a) El-Faham, A.; Albericio, F. Chem. Rev. 2011, 111, 6557–6602. (b) Ottenheijm, H. C. J.;
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Bosshard, H. H.; Mory, R.; Schmid, M.; Zollinger, Hch. Helv. Chim. Acta. 1959, 42, 1653–
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