Organocatalyzed intramolecular carbonyl-ene reactions

Article abstract of DOI:10.3390/molecules21060713

An organocatalyzed intramolecular carbonyl-ene reaction was developed to produce carbocyclic and heterocyclic 5- and 6-membered rings from a citronellal-derived trifluoroketone and a variety of aldehydes. A phosphoramide derivative was found to promote the cyclization of the trifluoroketone, whereas a less acidic phosphoric acid proved to be a superior catalyst for the aldehyde substrates.

Full text of DOI:10.3390/molecules21060713

molecules
Communication
Organocatalyzed Intramolecular
Carbonyl-Ene Reactions
Heidi A. Dahlmann, Amanda J. McKinney, Maria P. Santos and Lindsey O. Davis *
Department of Chemistry and Biochemistry, Berry College, P.O. Box 495016, Mt. Berry, GA 30149, USA;
hdahlmann@berry.edu (H.A.D.); amanda.mckinney@vikings.berry.edu (A.J.M.);
maria.santos@vikings.berry.edu (M.P.S.)
*
Correspondence: ldavis@berry.edu; Tel.: +1-706-236-2237
Academic Editor: Raquel P. Herrera
Received: 2 May 2016; Accepted: 27 May 2016; Published: 31 May 2016
Abstract: An organocatalyzed intramolecular carbonyl-ene reaction was developed to produce
carbocyclic and heterocyclic 5- and 6-membered rings from a citronellal-derived trifluoroketone
and a variety of aldehydes. A phosphoramide derivative was found to promote the cyclization of
the trifluoroketone, whereas a less acidic phosphoric acid proved to be a superior catalyst for the
aldehyde substrates.
Keywords: organocatalysis; carbonyl-ene; phosphoric acid; N-triflylphosphoramide
1
. Introduction
The carbonyl-ene reaction is a well-studied transformation in organic chemistry, as it affords
an atom-economical method for synthesizing homoallylic alcohols [
been used to catalyze this reaction [ ], but organocatalysis has recently emerged as a powerful means
for facilitating many organic transformations [ ], including carbonyl-ene reactions. Clarke and
co-workers developed the first organocatalyzed carbonyl-ene reaction using the Schreiner catalyst [ ],
a thiourea derivative [ ]. An asymmetric variant was then developed by Rueping et al. using a chiral
N-triflylphosphoramide [ ]. The reaction yielded -hydroxyesters in good yield and enantioselectivity,
1]. Traditionally, Lewis acids have
2,3
4–6
7
8
9
α
but the scope was limited to intermolecular reactions and required the use of an activated
enophile. Recently, List and co-workers reported an intramolecular carbonyl-ene cyclization to afford
pyrrolidines, tetrahydrofurans, and cyclopentanes using a chiral imidodiphosphate catalyst [10]. While
this report serves as a hallmark for Brønsted-acid-catalyzed intramolecular carbonyl-ene reactions, the
scope was limited to the formation of the kinetically-favored five-membered rings [11]. The majority
of these products were pyrrolidines derived from N-tosylated aminoaldehyde, the parent molecule
which was known to spontaneously undergo intramolecular carbonyl-ene cyclization [12], while
less activated substrates required up to 11 days to reach completion. Noting the utility of this
reaction, but also the limitations of current reports, we set out to develop a Brønsted-acid-catalyzed
intramolecular carbonyl-ene reaction with a complementary substrate scope and faster reaction times.
Herein, we describe organocatalyzed intramolecular carbonyl-ene reactions that produced carbocyclic
and heterocyclic 5- and 6-membered rings.
2
. Results and Discussion
We began our investigation by screening a variety of Brønsted acids for their ability to cyclize
citronellal-derived trifluoromethylketone
previous reports of trifluoropyruvate derivatives serving as carbonyl-acceptors in intermolecular
carbonyl-ene reactions [ ]. Simple Brønsted acid catalysts such as H PO and HCl were unable to
catalyze the reaction at an acceptable rate, producing little to no product within 24 h (Table 1, Entries 1
1 (Table 1), selecting this activated substrate based on
8,9
3
4
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Molecules 2016, 21, 713
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and 2) [13]. Similarly, the phosphoric acid derivative diphenyl phosphate (Figure 1, 3a), induced very
slow conversion of substrate, resulting in a low yield of ene product (Table 1, Entry 3). In contrast, the
more acidic N-triflyl phosphoric amide 3b (Figure 1) catalyzed the reaction at a significantly higher
rate, resulting in complete conversion and good yields in as few as 7 h (Table 1, Entries 4 and 8) [14].
Notably, we were able to decrease the catalyst loading from 0.5 to 0.2 equivalents without a significant
loss in yield (Table 1, Entries 4 and 5). Decreasing the concentration of the reaction resulted in a longer
reaction time with a small drop in yield (Table 1, Entries 6 and 7).
Figure 1. Brønsted acids screened for carbonyl-ene reaction.
Table 1. Optimization of carbonyl-ene cyclization of trifluoroketone 1.
O
HO CF3
HO CF3
catalyst
CF3
1
rac-2a
rac-2a'
Entry 1
Catalyst
Equiv. of Catalyst [1] (M)
t (h)
Yield 2 2 (%) d.r. (2a:2a )
1
3
1
2
3
4
5
6
7
8
H PO4
HCl
3a
3b
3b
3b
3b
3b
1
1
2
2
2
2
2
2
0.5
2
24
24
24
24
24
24
48
7
0
-
-
2:1
2:1
3
13
25
84
86
69
75
79
0.5
0.5
0.2
0.1
0.1
0.5
2:1
2.1:1
2.1:1
2.2:1
1
All reactions were run in anhydrous dichloromethane at 25 C. 2 The yield is reported as a mixture of
˝
1 1
diastereomers 2a/2a ; however, products 2a and 2a can be separated using column chromatography (see
Material and Methods Section). The diastereomeric ratios (2a:2a ) were determined using H-NMR integration
3
1
1
of isolated products.
Concurrently, we screened Brønsted acids for their ability to catalyze the cyclization of citronellal
(4a). While citronellal is less activated than the corresponding trifluoromethyl ketone, it serves as the
prototypical substrate for a Type I carbonyl-ene cyclization, as it is commercially available [15–17].
Surprisingly, the use of phosphoramide 3b resulted in the isolation of a complex mixture of products
with only a trace yield of ene product 5a and no starting material recovery (Table 2, Entry 1). Diethyl
phosphate (3c) successfully promoted the reaction, albeit slowly, resulting in a low yield and a 77%
recovery of starting material after 24 h (Table 2, Entry 2). We were pleased to find a significant
increase in reaction rate and yield after 24 h when phosphoric acid derivative 3a was used as a catalyst.
Under these mild reaction conditions [18], isopulegol (5a) was the primary diastereomer isolated
1
from the reaction mixture in addition to a small amount of neoisopulegol (5a ), typically in a 2:1 ratio
Entries 3–5). A similar yield of product 5a was obtained when only 0.06 equivalents of catalyst were
(
used at a higher concentration (0.5 M) compared to 0.5 equivalents at 0.1 M, but a decreased selectivity
was observed in the isolated products (compare Entries 3 and 4) [19]. At an even higher substrate
concentration (2 M), additional uncharacterized products were formed and the yield of 5a decreased
considerably (Table 2, Entry 5).

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Table 2. Optimization of carbonyl-ene cyclization of citronellal 4a.
O
OH
OH
catalyst
H
4a
rac-5a
rac-5a'
Entry 1
Catalyst
Equiv. of Catalyst
[4a] (M)
t (h)
Yield 5a 2 (%)
d.r. (5a:5a )
1
3
1
2
3
4
5
3b
3c
3a
3a
3a
1
0.1
0.1
0.1
0.6
2
24
24
22
24
18
trace
14
61
65
31
-
1:1
2.4:1
1.5:1
2:1
0.5
0.5
0.06
0.1
1
All reactions were run in anhydrous dichloromethane at 25 C. 2 The yield is reported as a mixture of
˝
1 1
diastereomers 5a/5a ; however, products 5a and 5a can be separated using column chromatography (see
Material and Methods section). The diastereomeric ratios (5a:5a ) were determined using H-NMR integration
3
1
1
of isolated products.
Once the cyclization of the aldehyde substrate was optimized (0.5 equiv of 3a, 0.1 M, 24 h, rt),
the scope of the reaction was explored. The carbonyl-ene reaction proceeds with excellent yield
to give 3,4-disubstituted piperidine product 5b (Table 3, Entry 1), favoring the trans diastereomer.
Aryl aldehyde 4c, which required a full equivalent of 3a to undergo complete conversion within
2
4 h, afforded a moderate yield of the carbonyl-ene product 5c (again with the trans product
favored over the cis product) as well as a substantial amount (~17%) of the conjugated diene,
-isopropenyl-1,2-dihydronaphthalene, that resulted from an elimination reaction (Table 3, Entry 2).
3
Lastly, the cyclization of commercially available 2,6-dimethyl-5-heptenal (4d) resulted in the formation
of five-membered ring 5d with great diastereoselectivity, albeit in only moderate yield (Entry 3). The
reaction conditions have been modified in an attempt to increase the yield of the carbonyl-ene product;
however, in each case, a complex mixture of products was isolated with no starting material recovered.
Table 3. Scope of the carbonyl-ene reaction of aldehydes.
Entry 1
Aldehyde
Product
Yield (%) (d.r.) 2,3
1
89 (2.7:1)
2 4
44 (3.3:1)
3
37 (>10:1)
1
˝
5
Unless otherwise noted, reactions were run in anhydrous dichloromethane at 25 C for 19–24 h with [
4
] = 0.1 M
2
1
and 0.5 equivalents of 3a
.
The yield is reported as a mixture of diastereomers
5/
; however, the diastereomeric
products of 5b and 5c can be separated using column chromatography (see Material and Methods section).
3
1
1
The diastereomeric ratios (trans:cis; 5:5 ) were determined using H-NMR integration of isolated products.
1
4
The methyl group of the minor diastereomer 5d is cis to the hydroxyl group. One molar equivalent of 3a
was used.

Molecules 2016, 21, 713
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3
. Materials and Methods
3
.1. General
Citronellal (93%) was obtained from Acros and was purified with normal-phase column
chromatography. 2,4-dimethylheptenal (80%) was purchased from Aldrich and was purified
via normal phase chromatography before use. Diphenyl phosphate (3a) was purchased from
Aldrich. Trifluoromethyl ketone
1 was prepared from citronellic acid as previously described [20].
Diphenylphosphoramide (3b) was prepared as previously described [21]; following chromatographic
purification, catalyst 3b was washed with 6 M of HCl and extracted with chloroform to ensure
protonation of the catalyst, as discussed for the preparation of related N-triflylphosphoramide
catalysts [22]. 2-(4-methyl-3-pentenyl)benzaldehyde [23] and 4-methyl-N-(3-methylbut-2-enyl)-
N-(3-oxopropyl)benzenesulfonamide [24] were prepared as previously described. Anhydrous
dichloromethane was obtained from a solvent system purchased by Pure Process Technology.
Normal-phase flash-chromatography was carried out manually on silica gel (Mallinckrodt Chemicals,
6
0 Å, 40–63 micron) or with a Combi-flash MPLC system equipped with Redi-Sep Gold
1
chromatography cartridges. H-NMR spectra were obtained by using a Jeol 400 MHz spectrometer
(Jeol USA, Inc., Peabody, MA, USA). Chemical shifts are reported in parts per million relative to TMS.
Coupling constants were reported in Hertz, and multiplicities were indicated using the following
symbols: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), ddd (doublet of doublets
of doublets), etc. 13C-NMR data was obtained using Jeol 400 MHz NMR operating at 100 MHz.
1
13
All products were characterized by H-NMR and C-NMR and compared with available literature
1
data. High-resolution mass spectra (HRMS) of 2a/a were obtained on a Thermo LTQ-FTMS instrument
(ThermoFisher Scientific, Waltham, MA, USA).
3
.2. General Procedure for Intramolecular Carbonyl-Ene Reactions
Aldehyde or CF -ketone substrate (0.4–2 mmol), catalyst
3
(0.1–1 equivalents), and anhydrous
3
dichloromethane (0.1–2 M with respect to aldehyde) were added to a small glass vial containing a stir
bar. After stirring at room temperature for 24–48 h, the reaction was concentrated and purified by
column chromatography.
1
3
.2.1. Synthesis of Compounds 2a/a
1
Compounds 2a
CF ketone
/
a
were prepared according to the above-described general procedure by stirring
1
(208 mg, 1 mmol) and diphenylphosphoramide 3b (76 mg, 0.2 mmol) in anhydrous
3
dichloromethane (0.5 mL) at room temperature for 24 h to provide a mixture of diastereomers as
a colorless oil in 86% yield (flash-chromatography: 20% diethyl ether in petroleum ether). Retention
1
factor of 2a
/
2a = 0.3 (5% ethyl acetate: 95% hexanes). The relative stereochemical assignments of
1
2
a
/
2a were made on the basis of coupling constants for H2 and H6ax 25]. For 2a, the coupling
[
constants for H2 = 3.6 and 12.8 Hz indicated axial orientation, and the coupling constants for
H6ax = 12.4 and 14.0 Hz indicated axial-axial splitting with H5 and germinal coupling. Therefore, H5
1
must be in the axial position and trans to H2. For 2a , H2 had a coupling constant of 13.2 Hz, indicating
axial orientation, and one of the coupling constants for H6ax = 4.5 Hz indicated axial-equatorial
1
splitting with H5. Therefore, H5 must be in the equatorial position and cis to H2. H-NMR of
2a (400 MHz, CDCl3): δ 4.94 (s, 1H, vinylic H); 4.83 (s, 1H, vinylic H); 2.37 (s, 1H, -OH); 2.25 (dd, J = 3.7,
1
1
1
2.7 Hz, 1H, H2); 1.96 (ddd, J = 1.8, 3.2, 13.9 Hz, 1H, H6eq); 1.84 (m, 1H, H5eq); 1.83 (s, 3H, vinylic Me);
.80 (m, 1H, H3eq); 1.73 (m, 1H, H4eq); 1.55 (m, 1H, H3ax); 1.18 (ddd, J = 1.9, 12.4, 13.9, H6ax); 0.94 (m,
H, H4ax); 0.93 (d, J = 8.0 Hz, 3H, C5-Me). 13C-NMR (100 MHz):
δ 147.6 (vinylic C); 126.1 (q, J = 290 Hz,
-
CF ); 112.2 (vinylic C); 74.3 (q, J = 26 Hz, C1); 46.3 (C2); 39.0 (C6); 34.3 (C4); 28.5 (C3); 26.5 (C5); 24.2
3
(
vinylic Me); 21.9 (C5-Me). HRMS, APCI: Calcd. for C H F O (M+): 222.12315; found: 223.13509.
11 17 3
1
1
H-NMR of 2a (400 MHz):
δ 5.01 (m, 1H, vinylic H); 4.90 (m, 1H, vinylic H); 2.92 (s, 1H, -OH); 2.31
(m, 1H, H2); 2.25 (ddd, J = 1.9, 3.4, 13.6 Hz, 1H, H6eq); 1.89 (m, 1H, H3eq); 1.82 (m, 1H, H4eq); 1.75 (s,

Molecules 2016, 21, 713
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3
(
(
2
H, vinylic Me); 1.73 (m, 1H, H5); 1.66 (m, 1H, H3ax); 1.125 (tq, J = 2.4, 2.4, 2.4, 13.6, 13.6 Hz, H6); 1.00
m, 1H, H4ax); 0.94 (d, J = 6.5 Hz, 3H, C5-Me). 13C-NMR (100 MHz, CDCl3):
144.1 (vinylic C); 126.6
q, J = 286 Hz, -CF ); 115.7 (vinylic C); 73.0 (q, J = 27 Hz, C1); 53.2 (C2); 42.2 (C6); 34.1 (C4); 28.2 (C5);
δ
3
+
+
6.3 (C3); 22.4 (C5-Me); 19.7 (vinylic Me). HRMS, ESI: Calcd. for C H F O (M + H ): 223.13043;
11 18 3
found: 223.13041.
1
.2.2. Synthesis of Compounds 5a/a
3
1
Compounds 5a/a were prepared according to the above-described general procedure by stirring
citronellal (101.5 mg, 0.658 mmol) and diphenyl phosphate (3a) (82.0 mg, 0.328 mmol) in anhydrous
dichloromethane (6.6 mL) at room temperature for 22 h to provide a colorless oil in a 61% yield
(
products were purified by flash-chromatography with 10% diethyl ether in petroleum ether). The NMR
1
1
spectra of isopulegol (5a) and neoisopulegol (5a ) matched those previously reported [26]. H-NMR of
isopulegol ((1 , 2 ,5 )-5-methyl-2-(1-methylethenyl)cyclohexanol, 5a) (400 MHz, CDCl3): 4.91 (m,
H); 4.86 (br s, 1H); 3.46 (dt, J = 4.3, 10.4, 10.4 Hz, 1H); 2.04 (m, 1H); 1.89 (ddd, J = 3.4, 10.0, 12.8 Hz, 1H);
α
α
β
δ
1
1
(
5
2
.71 (d, J = 1.0 Hz, 3H); 1.65 (m, 2H); 1.48 (m, 2H); 1.34 (dt, J = 3.4, 12.4, 12.4 Hz, 1H); 0.96 (m, 2H); 0.95
1
d, J = 6.5 Hz, 3H). H-NMR of neoisopulegol ((1
α
, 2
4.95 (br s, 1H); 4.78 (br s, 1H); 3.98 (m, 1H); 1.98 (m, 2H); 1.79 (s, 3H); 1.73 (m,
H); 1.55 (br s, 1H); 1.45 (m, 1H); 1.12 (m, 1H); 0.95 (m, 2H); 0.88 (d, J = 6.4 Hz, 3H).
α
, 5
β
)-5-methyl-2-(1-methylethenyl)cyclohexanol,
1
a ) (400 MHz, CDCl3): δ
1
.2.3. Synthesis of Compounds 5b/b
3
1
Compounds 5b/b were prepared according to the above-described general procedure by using
-methyl-N-(3-methylbu-2-enyl)-N-(3-oxopropyl)benzenesulfonamide (106.3 mg, 0.378 mmol) and
4
diphenyl phosphate (3a) (48 mg, 0.192 mmol) in anhydrous dichloromethane (3.8 mL) at room
temperature for 24 h to provide an oil in a 89% yield (products were purified by flash-chromatography
with a stepwise gradient of 20%–30% ethyl acetate in hexanes). The NMR spectra of isolated piperidines
1
matched those previously reported [13]. H-NMR of trans-3-isopropenyl-1-(toluene-4-sulfonyl)
piperidin-4-ol, 5b, (400 MHz, CDCl3):
H); 4.89 (s, 1H); 3.84 (m, 1H); 3.76 (m, 1H); 3.44 (dt, J = 4.5, 10.1, 10.1 Hz, 1H); 2.44 (s, 3H); 2.37 (dt,
J = 2.8, 12.4, 12.4 Hz, 1H); 2.26 (dt, J = 3.4, 11, 11 Hz, 1H); 2.17 (t, J = 11 Hz); 2.04 (m, 1H); 1.71 (s, 3H);
δ 7.64 (d, J = 8.0 Hz, 2H); 7.32 (d, J = 8.0 Hz, 2H); 5.01 (s,
1
1
1
1
.64 (m, 1H). H-NMR of cis-3-isopropenyl-1-(toluene-4-sulfonyl)piperidin-4-ol, 5b (400 MHz, CDCl3):
δ
7.66 (d, J = 8.1 Hz, 2H); 7.32 (d, J = 8.1 Hz, 2H); 4.99 (s, 1H); 4.59 (s, 1H); 3.97 (m, 1H); 3.59 (m, 2H);
.60 (dt, J = 3.1, 12, 12 Hz, 1H); 2.57 (t, J = 11.5 Hz, 1H); 2.42 (s, 3H); 2.37 (d, J = 12.1 Hz, 1H); 1.96 (dq,
2
J = 2.8, 2.8, 2.8, 13.9 Hz, 1H); 1.87 (m, 1H); 1.77 (s, 3H).
1
3
.2.4. Synthesis of Compounds 5c/c
1
Compounds 5c
/c
were prepared according to the above-described general procedure by using
2
0
-(4-methyl-3-pentenyl)benzaldehyde (123.6 mg, 0.656 mmol) and diphenyl phosphate (3a) (183.0 mg,
.656 mmol) in anhydrous dichloromethane (7.3 mL) at room temperature for 24 h to provide a mixture
of diastereomers in a 44% yield (products were purified by flash-chromatography with a stepwise
gradient of 0%–1% diethyl ether in petroleum ether). The NMR spectra of alcohol products (5c
1
1
and 5c ) [27], and the elimination product [28] matched those previously reported. H-NMR of
trans-2-isoprenyl-1,2,3,4-tetrahydro-1-naphthalenol, 5c, (400 MHz, CDCl3): 7.61 (d, J = 7.6 Hz,
H); 7.23 (m, 1H); 7.19 (m, 1H); 7.09 (d, J = 7.2 Hz, 1H); 4.96 (m, 1H); 4.89 (m, 1H); 4.70 (d,
δ
1
J = 9.5 Hz, 1H); 2.89 (ddd, J = 5.5, 11.2, 16.7 Hz, 1H); 2.82 (ddd, J = 3.2, 5.4, 16.7 Hz, 1H); 2.39
1
(
ddd, J = 3.1, 9.5, 11.8 Hz, 1H); 2.07 (br s, 1H); 1.93 (m, 1H); 1.83 (m, 1H); 1.81 (s, 3H). H-NMR of
1
cis-2-isoprenyl-1,2,3,4-tetrahydro-1-naphthalenol, 5c (400 MHz, CDCl3):
δ 7.38 (dd, J = 2.1, 7.0 Hz, 1H);
7.23 (m, 1H); 7.22 (m, 1H); 7.16 (m, 1H); 5.08 (m, 1H); 4.91 (m, 1H); 4.76 (m, 1H); 2.95 (ddd, J = 2.0, 5.4,
1
7.0 Hz, 1H); 2.81 (ddd, J = 5.9, 12.3, 17.0 Hz, 1H); 2.40 (m, 1H); 2.06 (dq, J = 5.4, 12.7, 12.7, 12.7 Hz,1H);
1
1
.91 (s, 3H); 1.79 (m, 2H). H-NMR of 3-isopropenyl-1,2-dihydronaphthalene (400 MHz, CDCl ):
δ 7.11
3
(m, 4H); 6.57 (s, 1H); 5.22 (s, 1H); 5.04 (s, 1H); 2.85 (t, J = 8 Hz, 2H); 2.53 (t, J = 8 Hz, 2H); 2.05 (s, 3H).

Molecules 2016, 21, 713
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1
.2.5. Synthesis of Compounds 5d/d
3
6
1
/d were prepared according to the above-described general procedure by using 2,
Compounds 5d
-dimethyl-5-heptenal (280 mg, 2 mmol) and diphenyl phosphate (3a) (250 mg, 1 mmol) in anhydrous
dichloromethane (20 mL) at room temperature for 19 h to provide a mixture of diastereomers in a 37%
yield (products were purified by flash-chromatography with a stepwise gradient of 5–20% diethyl ether
1
in petroleum ether). H-NMR of 5d (major isomer), (400 MHz, CDCl3):
δ 4.81 (d, J = 6.2 Hz, 2H); 3.4 (t,
J = 9.3 Hz, 1H); 2.38 (q, J = 9.3 Hz, 1H); 1.78–1.95 (m, 3H); 1.74 (bs, 1H, -OH); 1.73 (s, 3H); 1.5 (m, 1H);
1
3
1
1
.15 (m, 1H); 1.08 (d, J = 6.5 Hz, 3H). C-NMR (100 MHz):
δ
146.3, 110.8, 81.8, 55.0, 41.0, 29.3, 26.0, 19.7,
1
8.1. The NMR spectra of 5d/d match those previously reported for an analogous compound [29].
1
The protons of 5d overlapped with the major isomer (5d) except for H1, which appeared at 3.93 ppm,
and the β-methyl group at 1.00 ppm.
1
1
NMR spectra for products 2a/a and 5d/d can be found in the Supplementary Materials.
4
. Conclusions
In summary, we have reported organocatalyzed intramolecular carbonyl-ene cyclizations of
a citronellal-derived trifluoroketone and several aldehydes. The scope of this reaction is more general
than previous reports and produces various trans–configured carbocyclic and heterocyclic 5- and
6-membered rings in moderate-to-good yield. In addition, these reactions are complete within 7–24 h.
Further exploration of the scope of the reaction as well as screening enantioselective catalysts are
ongoing in our laboratory.
Supplementary Materials: Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/21/
6
/713/s1.
Acknowledgments: Acknowledgement for financial support is made to Berry College (start-up funds and Faculty
Development Grant) and the National Science Foundation (CHE-1125616). M.P.S. would like to thank the Richards
family for partial support of this project.
Author Contributions: This project was developed and designed by L.O.D. Undergraduate co-authors A.J.M.
and M.P.S. contributed equally to the experimentation and result analysis under the direction of both L.O.D. and
H.A.D. H.A.D. contributed to experimentation, analysis of results, and manuscript preparation.
Conflicts of Interest: The founding sponsors had no role in the design of the study; in the collection, analyses, or
interpretation of data; in the writing of the manuscript; or in the decision to publish the results.
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Sample Availability: Samples of the Compounds 2 and 5b–d are available from the authors.
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