Synthesis of N,O-acetals by net amide C[sbnd]N bond insertion of aldehydes into N-acyl phthalimides and N-acyl azoles

Article abstract of DOI:10.1016/j.tet.2016.08.041

We found that N-acyl phthalimides and several N-acylated azoles are capable of reacting with aldehydes to form O-acyl-N,O-acetals in an apparent amide C[sbnd]N bond insertion. In the context of N-acyl phthalimides, the reaction is mediated by substoichiometric amounts of sodium iodide and potassium phthalimide. DFT computations supported a proposed mechanism and provided insights into the effect of the alkali metal additive. This strategy could be used to prepare a myriad of N,O-acetals from a range of aldehydes. A one-pot procedure was also developed in which N-acyl phthalimide was generated in situ prior to forming the N,O-acetal product. The one-pot strategy was used to demonstrate that activated amides derived from imidazole, pyrazole, (benzo)triazole, and tetrazole are also amenable substrates. Collectively, these studies provide an approach to the synthesis of a variety of N,O-acetals under mild conditions from inexpensive starting materials.

Full text of DOI:10.1016/j.tet.2016.08.041

Accepted Manuscript
Synthesis of N,O-acetals by net amide C-N bond insertion of aldehydes into N-acyl
phthalimides and N-acyl azoles
Robert N. Enright, Jeffrey L. Grinde, Lincoln I. Wurtz, Matthew S. Paeth, Tekoa R.
Wittman, Emily R. Cliff, Yessra T. Sankari, Lucas T. Henningsen, Chuchen Tan,
Joseph D. Scanlon, Patrick H. Willoughby
PII:
S0040-4020(16)30817-1
10.1016/j.tet.2016.08.041
TET 28022
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 7 July 2016
Revised Date: 4 August 2016
Accepted Date: 12 August 2016
Please cite this article as: Enright RN, Grinde JL, Wurtz LI, Paeth MS, Wittman TR, Cliff ER, Sankari YT,
Henningsen LT, Tan C, Scanlon JD, Willoughby PH, Synthesis of N,O-acetals by net amide C-N bond
insertion of aldehydes into N-acyl phthalimides and N-acyl azoles, Tetrahedron (2016), doi: 10.1016/
j.tet.2016.08.041.
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Synthesis of N,O-Acetals by Net Amide C–N
Bond Insertion of Aldehydes into N-Acyl
Phthalimides and N-Acyl Azoles
Leave this area blank for abstract info.
Robert N. Enright, Jeffrey L. Grinde, Lincoln I. Wurtz, Matthew S. Paeth, Tekoa R. Wittman, Emily R. Cliff,
Yessra T. Sankari, Lucas T. Henningsen, Chuchen Tan, Joseph D. Scanlon, and Patrick H. Willoughby*
Chemistry Department, Ripon College, 300 W Seward St., Ripon, Wisconsin 54971, United States

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Tetrahedron
journal homepage: www.elsevier.com
Synthesis of N,O-Acetals by Net Amide C–N Bond Insertion of Aldehydes into N-
Acyl Phthalimides and N-Acyl Azoles
Robert N. Enright, Jeffrey L. Grinde, Lincoln I. Wurtz, Matthew S. Paeth, Tekoa R. Wittman, Emily R.
Cliff, Yessra T. Sankari, Lucas T. Henningsen, Chuchen Tan, Joseph D. Scanlon, and Patrick H.
Willoughby*
Chemistry Department, Ripon College, 300 W Seward St., Ripon, Wisconsin 54971, United States
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
We found that N-acyl phthalimides and several N-acylated azoles are capable of reacting with
aldehydes to form O-acyl-N,O-acetals in an apparent amide C–N bond insertion. In the context
of N-acyl phthalimides, the reaction is mediated by substoichiometric amounts of sodium iodide
and potassium phthalimide. DFT computations supported a proposed mechanism and provided
insights into the effect of the alkali metal additive. This strategy could be used to prepare a
myriad of N,O-acetals from a range of aldehydes. A one-pot procedure was also developed in
which N-acyl phthalimide was generated in situ prior to forming the N,O-acetal product. The
one-pot strategy was used to demonstrate that activated amides derived from imidazole,
pyrazole, (benzo)triazole, and tetrazole are also amenable substrates. Collectively, these studies
provide an approach to the synthesis of a variety of N,O-acetals under mild conditions from
inexpensive starting materials.
Available online
Keywords:
N,O-Acetal Synthesis
C–N Insertion
Acyl Phthalimide
Acyl Azole
2009 Elsevier Ltd. All rights reserved
.
1. Introduction
N,O-Acetals are a privileged functionality because of their (i)
role in the bioactivity of medicinally-relevant molecules and (ii)
usefulness as a synthetic building block for the preparation of
complex nitrogen-containing compounds. There are numerous1
bioactive natural products with an N,O-acetal moiety including,
for example, cytotoxic agents psymberin (i.e., irciniastatin A, 1,
Figure 1a)2 and pederin (2).3 Recently, structure-activity studies
by Floreancig and co-workers demonstrated that the N,O-acetal
moiety of 1 and 2 was necessary for potent bioactivity.4 In the
context of organic synthesis, N,O-acetals have proven to be
useful surrogates of imines because the oxygen functionality is
readily activated under acidic conditions allowing for substitution
by a variety of nucleophiles (cf. Figure 1b).5 N-Acylated variants
of N,O-acetals have proven particularly useful because they are
generally bench stable unlike their N-acyl imine counterparts,
which are highly susceptible to hydrolysis by adventitious water.
Recently, Doyle6 expanded the utility of N,O-acetals in organic
synthesis by reporting a Ni-catalyzed cross coupling of N-
acylated N,O-acetals (e.g., 3) with arylboroxines to give 2-aryl
quinolines (e.g., 4). A related procedure reported by Lautens7
describes a Pd-catalyzed arylation of trifluoromethyl-containing
N,O-acetals. Collectively, these points demonstrate that the
medicinal chemistry and organic synthesis communities would
continue to benefit from additional approaches to prepare N,O-
acetals.
Figure 1: N,O-Acetals are (a) a critical functional group to
bioactive natural products, (b) useful electrophiles in organic
synthesis, and (c) participants in transition metal-catalyzed cross
coupling reactions.

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Tetrahedron
Numerous reports have described methods for preparing a
Acylation of 16 by N-acyl phthalimide 7 gives rise to the
observed product, 8a, and regenerates phthalimide anion. The
proposed mechanism suggests that 15 is serving as a catalyst
because the liberated phthalimide anion can subsequently engage
another molecule of aldehyde to form N,O-acetal product and
regenerate additional 15. To account for the initial concentration
of the phthalimide anion catalyst, we also propose that the
reaction is initiated by hydrolyzing a sacrificial amount of N-acyl
phthalimide with an OH donor (cf. Figure 3c). For example,
variety of N-acylated N,O-acetals.8 Herein we report conditions
that effect the synthesis of N,O-acetals from N-acyl phthalimides
(cf. 5, Figure 2) and acyl azoles. The resulting products appear to
arise via insertion of the aldehyde carbonyl into the amido C–N
bond, providing a novel approach to making O-acyl-N-imido-
N,O-acetals (e.g., 6). Known strategies for making this family of
phthalimide-containing N,O-acetals involve decarboxylative
acetoxylation of α-phthalimdo acids with stoichiometric lead8c or
radical intermediates.8g The conditions described in this report
are mild (i.e., substoichiometric NaI and potassium phthalimide)
and complement previous methods by using aldehyde starting
materials. This report also includes a detailed mechanistic
analysis, optimization studies for general reaction conditions, a
one-pot procedure that uses commercially available starting
materials, and a thorough evaluation of substrate scope.
hydrolysis of N-acyl phthalimide
7 in the presence of
adventitious water would release 15 after proton transfer to
triethylamine. Alternatively, initiation could occur by acyl
transfer to i) the enol content of isobutyraldehyde and/or ii) a
carboxylate impurity from aldehyde autoxidation. Under the
proposed mechanism, Et3N discourages formation of neutral
phthalimide, which would likely not engage aldehyde in the
proposed mechanism.
Figure 2: Methodology described in this report for the synthesis
of N-phthalimido-O-acyl-N,O-acetals by reaction between N-acyl
phthalimides and aldehydes.
2. Results and Discussion
As part of a study into the reactivity of N-acyl phthalimides
with aldehydes, we found that treating a mixture of N-acetyl
phthalimide (7, Scheme 1) and isobutyraldehyde with Et3N and
LiBF4 led to the unexpected formation of N,O-acetal 8a. We
initially speculated that we had simply expanded the scope of
conditions previously reported Katritzky in which N,O-acetals
were formed by treating acyl benzotriazoles with an aldehyde and
K2CO3.9 However, product was not observed when we applied
Katritzky’s conditions (i.e., 0.25 equiv of K2CO3 in MeCN) to the
synthesis of 8a. When the K2CO3 loading was increased to 1
equiv, the yield of 8a improved to only 8%.10 It was not
immediately clear why use of N-acyl phthalimide 7 led to
diminished reaction efficiency under Katritzky’s conditions.
However, it was encouraging that the combination of LiBF4 and
Et3N gave product in moderate yield, suggesting that similar
conditions could provide a general approach to making N,O-
acetals from amides.
Scheme 1. Synthesis of N,O-acetal 8a by net C–N bond insertion
of isobutyraldehyde into N-acyl phthalimide 7
Figure 3: Mechanistic studies and resulting hypotheses: (a) a
double label crossover experiment (b) a proposed mechanism for
the conversion of N-acyl phthalimides into N,O-acetals (c) an
initiation pathway in which an OH donor converts a sacrificial
amount of N-acyl phthalimide into phthalimide anion.
Prompted by the unusual nature of the transformation, we
initially turned our attention to the mechanism. We performed a
double label crossover experiment in which a mixture of
isobutyraldehyde and N-acyl phthalimides 9 and 10 was treated
with LiBF4 and triethylamine (cf. Figure 3a). 1H NMR and
LC/MS analysis clearly showed that the reaction gave rise to a
mixture of the four possible N,O-acetal products (i.e., 11-14).
The positive crossover experiment indicated that phthalimide
dissociates during the course of the reaction, and led us to
propose the mechanism depicted in Figure 3b. Specifically, the
liberated phthalimide anion (i.e., 15, shown with metal
counterion M+) adds to the aldehyde to form alkoxide adduct 16.
Guided by the proposed mechanism, we turned to optimizing
the reaction in the presence of catalytic metal phthalimide (cf.
Table 1). To avoid competitive initiation by an enol, we
performed the optimization studies with non-enolizable
benzaldehyde, which gave N,O-acetal product 8b. Additionally,
4Å molecular sieves were used to remove water, and
benzaldehyde was freshly distilled to remove autoxidation
impurities. Early optimization studies indicated that a 1:1
cosolvent mixture of acetonitrile and ethyl acetate gave improved
yields. Substituting LiBF4 and Et3N for 10 mol% potassium
phthalimide (PhtNK) led to a reduced yield of 39% (cf. entry 1,
Table 1). This result was encouraging because it demonstrated

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that a substoichiometric amount of metal phthalimide anion was
capable of promoting reaction. No reaction was observed when
PhtNK was omitted or phthalimide (N–H) was used, the later
result supported the notion that Et3N was initially (cf. Scheme 1)
required to ensure the presence of phthalimide anion.11
Screening a number of stoichiometric additives (cf. entries
2–11) and phase transfer reagents (cf. entries 12 and 13) led to a
wide range of yields. Use of NaI gave the highest yield of 80%.
This led us to study the ability of NaI to perform as a
substoichiometric additive, and use of 10 mol% led to a slightly
reduced yield of 68% (cf. entry 14). Use of 10 mol% of other
alkali metal salts gave lower yields, ranging between 1–51% (cf.
entries 15–23). We settled on the use of 20 mol% of both PhtNK
and NaI, which gave 81% (cf. entry 24) yield and was similar to
that obtained when using stoichiometric NaI in combination with
10 mol% of PhtNK (cf. entry 6).
Table 1. Reaction Optimization
The additive screen revealed an interesting trend with
respect to the effect of the metal cation on reaction efficiency.
Namely, use of substoichiometric amounts of soluble sodium
salts (e.g., NaI and NaOAc) gave better yields than the
corresponding potassium salts. Additionally, 10 mol% NaI gave
higher yields than stoichiometric amounts of either LiI or LiBF4.
We suspected that NaI was providing an alternative counterion
for the phthalimide catalyst, which would mean that sodium
phthalimide could also be an efficient catalyst. This was
confirmed by substituting potassium phthalimide with 10 mol%
sodium phthalimide, which gave product in 52% yield (cf. entry
25). Additionally, lithium phthalimide was also used directly,
which gave product in much lower yield (cf. 11%) than when
either the potassium or sodium salts were used.13 While it is not
unexpected that the reaction yield be highly dependent on the
metal counterion, it is interesting that use of lithium additives led
to a much less efficient reaction.
1
b
aYields were determined by H NMR. The loading of both NaI
c
and PhtNK was increased to 20 mol%. PhtNK was replaced by
10 mol% of the indicated additive.12
20‡
11.7
18 ‡
22‡
9.1
10.0
M = Na+
Li+
K+
8.8
7.5
1.5
6.9
5.9
5.5
24‡
2.5
3.6
3.7
2.5–3.2
3.2
2.6
1.0
17
M
0.9
0.0
O
15
O
-2.2
-2.7
(PhtNM)
N
19
O
-4.5
21
M
-4.5
-4.7
O
M
O
M
23
N
O
O
+PhtNAc (7)
N
O
N
O
-8.5
O
O
O
+PhtNAc (7)
N
O
O
O
-10.9
O
N
+PhtNAc (7)
+CH2O
-11.4
O
CH3
O
O
N
8c
M
OAc
O
PhtN
-18.7
+PhtNM
(PhtNM)2
(15)2
O
O
M
N
N
M
O
1.970 Å
20‡-Na
23-Na
O
Figure 4. Relative free energies for the metal phthalimide-mediated reaction between N-acyl phthalimide 7 and formaldehyde to give
N,O-acetal 8c. Pathways involving Li+, Na+, and K+ are indicated with different colors. Representative 3D structures of 20‡ and 23 with
sodium counterion are included to depict sodium coordination (cf. hashed lines to sodium) and π-stacking in 23. DFT calculations were
performed using M06/6-31+G(d,p)14 with an automatically generated density fitting basis set and the SMD solvation model15 (MeCN).
All free energies values are in kcal/mol.

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Tetrahedron
To provide support for the proposed reaction mechanism and
containing aldehyde, potassium phthalimide, and NaI gave the
corresponding N,O-acetal. It was crucial that the acid chloride
was the limiting reagent; otherwise, only N-acyl phthalimide and
trace yields of product were obtained. Additionally, it is
necessary to use NaI in excess because much of the soluble
sodium cation is likely sequestered as insoluble NaCl.
Monitoring the reaction by 1H NMR indicated that N-acyl
phthalimide (cf. 25) is rapidly formed and accumulates in the
reaction mixture before being converted into N,O-acetal.
gain insight into the alkali metal counterion effect, we turned to
DFT computations. Based on the mechanism proposed in Figure
3b, we computed the lowest energy paths for reaction between 7
and formaldehyde to give N,O-acetal 8c involving sodium, and
potassium counterions (cf. Figure 4). The lowest energy path
began with coordination (cf. 17) and adduct formation (via 18‡)
between formaldehyde and the phthalimide salt (15) to give
alkoxide 19. Acylation of 19 then proceeds through tetrahedral
intermediate 21 (via 20‡). We were unable to locate a transition
state that directly gave product from 21. Instead, we located π-
stacked tetrahedral intermediate 23 (via 22‡), which gave product
8c through a nearly barrierless transition state (cf. 24‡). The rate-
determining step for the pathway involving sodium counterion
(shown in blue) was formation of alkoxide adduct 19 with a
barrier of 6.3 kcal/mol from intermediate 17. In the case of the
potassium counterion (shown in grey), formation of intermediate
19 had a larger barrier of 7.1 kcal/mol from 17. It is noteworthy
that the barrier for formation of intermediate 21 increased from
3.9 to 5.8 kcal/mol when comparing the sodium and potassium
pathways.
Scheme 2. Aldehyde Scopea
Using the same approach, we computed the energetics of the
lithium phthalimide-mediated pathway (cf. red). Interestingly,
nearly all intermediates and transition states were substantially
lower in free energy than when calculated with sodium and
potassium counterions. This is in contrast to the experimental
results from our optimization studies in which use of lithium
phthalimide or lithium-containing additives gave sluggish
reactions and reduced yields. This led us to compute the energy
of a variety of aggregation states for lithium phthalimide. A
dimeric form (cf. 152) was found to be 18.7 kcal/mol lower in
energy than the lithium phthalimide monomer. Additionally,
metal phthalimide dimerization was found to be energetically
favorable in the sodium (i.e., -10.9 kcal/mol) and potassium (i.e.,
-8.5 kcal/mol) pathways. These results suggest that each pathway
involves uphill deaggregation of 152 prior to forming the N,O-
acetal product, albeit to a much greater extent for the lithium
pathway. Collectively, these results suggest why soluble lithium
salts are not as effective metal additives for this transformation.
aYields refer to isolated yields. bProduct was prepared on a
decagram scale. cReaction was performed with ca. 4–4.5 equiv of
aldehyde reactant. dReaction was performed with 1 equiv of
The scope of compatible aldehydes was evaluated using the
optimized conditions (cf. Scheme 2). In general, we found that
aliphatic (cf. 8a, 8c–h), cyclic (cf. 8i and 8j), and alkene-
containing (cf. 8k) aldehydes of varying substitution and steric
hindrance readily reacted with 7 to give N,O-acetals with yields
ranging from 38–85%. Successful use of hydroxycitronellal (cf.
8l) demonstrates that aldehydes with hindered alcohols are
capable of forming product.16 The formation of products 8b and
8m–8y indicate that aryl- and heteroaryl-containing aldehydes
also readily participate under the reaction conditions. Use of
electron rich aldehydes to give products 8w–8y resulted in poor
yields, which is likely due to an unfavorable equilibrium for
addition with phthalimide anion. This was overcome by adding a
stoichiometric amount of both NaI and potassium phthalimide,
which gave adequate yields ranging from 32–43%. To prepare
8z, ethyl glyoxalate, which readily polymerizes at room
temperature, was generated in situ by oxidative cleavage17 of
diethyl tartrate. The glyoxalate-containing mixture was then
treated with NaI and potassium phthalimide to give N,O-acetal 8z
in a net one-pot procedure.
f
Et3N. eProduct was prepared on a gram scale. Reaction was
g
performed with 1 equiv of NaI and PhtNK. The product was
prepared by a two-step, one-pot procedure involving oxidative
cleavage of ethyl glyoxalate prior to addition of 7, NaI, and
PhtNK (cf. Experimental Section).
The one-pot strategy was applied to a number of acid
chlorides to give products 8a, 11, 12, and 26a–h in good yields
(cf. Scheme 3a). Acid chlorides with a variety of steric hindrance
gave high yields (cf. 8a, 12, 26a–c). Use of benzyl chloroformate
gave 26d, indicating that O-acyloxy-N,O-acetals can also be
formed under the one-pot protocol. Benzoyl chlorides attached to
both electron withdrawing and donating groups readily gave
products 11 and 26e–26g. Additionally, bis-N,O-acetal 26h was
prepared using 0.5 equiv of adipoyl chloride. Collectively, these
results demonstrate that the one-pot procedure is a convenient
approach to preparing N,O-acetals without having to isolate the
N-acyl phthalimide precursor. However, it should be noted that
use of acetyl chloride under these conditions reproducibly gave a
lower yield (i.e., 57%) compared with the protocol involving N-
acyl phthalimide 7 (i.e., 79%). For this reason and because it is
both bench stable18 and readily prepared on a large scale (cf.
Experimental Section), 7 is generally our substrate of choice for
preparation of O-acetyl-N,O-acetals (cf. those in Scheme 2).
To gain insight into the scope of amenable N-acyl
phthalimides and enhance the operational simplicity of the
reported methodology, the optimized conditions were modified
so N,O-acetals could be obtained in a one-pot procedure (cf.
Scheme 3). Specifically, adding an acid chloride to a mixture

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By replacing potassium phthalimide with a heteroaromatic
privileged functionality in medicinal chemistry, are readily
prepared from inexpensive starting materials.
amine and Et3N, we were also able to demonstrate that other
activated amides form N,O-acetals under one-pot conditions (cf.
Scheme 3b). Specifically, N,O-acetals 27a–e were prepared in
one-pot from the corresponding amines. It is noteworthy that 27a
and 27c were not stable to chromatographic purification under a
number of attempted conditions. However, the one-pot procedure
delivered the crude products in >95% purity.
Scheme 4: Representative Synthetic Utility
Scheme 3. Scope of Acid Chloride and Nitrogen Source in the
One-Pot Synthesis of N,O-Acetalsa
3. Conclusion
Aldehydes are capable of reacting with N-acyl phthalimides
and N-acyl azoles to give N,O-acetals by a net C–N bond
insertion. Optimization studies indicated that the highest yields
are achieved when sodium cation is included, which was superior
to use of a number of other metal additives, including lithium and
potassium salts. DFT computational analysis supported the
proposed mechanistic hypothesis and was consistent with a
double label crossover experiment. Additionally, the
computations supported the optimization studies by indicating
that the most favorable energy path to products occurs with a
sodium counterion. A broad scope of aldehydes is capable of
participating in the reaction, and a one-pot procedure was
developed to further improve the operational simplicity of the
procedure. The one-pot procedure was also used to expand the
scope of products to include those derived from a variety of N-
acyl phthalimides and nitrogen-containing heterocycles. The
synthetic utility of the methodology was demonstrated by
showing that N,O-acetals prepared under the reported conditions
can be converted into known synthesis precursors to cetirizine
and rasagiline.
aYields refer to isolated yields. bReaction was performed by
adding acid chloride (1 equiv) to a co-solvent mixture of MeCN
and EtOAc (1:1) containing i-PrCHO, NaI, PhtNK, and 4Å MS
c
at room temperature. Reaction was performed with ca. 0.5 equiv
4. Experimental Section
d
of adipoyl chloride. Reaction was performed by adding benzoyl
General Comments: Solvents were dried prior to use by
distillation and/or storing over activated 3Å or 4Å molecular
sieves. Reactions performed with less than 5 mmole of starting
material were carried out in screw cap vials or culture tubes fitted
with a Teflon®-lined cap. Reactions requiring 4Å molecular
sieves (4Å MS) were performed using powdered 4Å MS that had
been “activated” by heating in a muffle furnace at 300 ºC for at
least 24 hours and stored in a desiccator.
chloride (1 equiv) to a co-solvent mixture of MeCN and EtOAc
(1:1) containing i-PrCHO, NaI, amine (R’2NH), Et3N, and 4Å
MS at room temperature prepared. eThe product was isolated as a
3:2 mixture of N1 (black attachment) and N2 (grey attachment)
regioisomers.
The N-phthalimido-O-acyl-N,O-acetals are themselves useful
because they can be readily converted into pharmaceutical
building blocks. For example, we found that treating N,O-acetal
8s with benzene and TiCl4 gave α-branched benzyl phthalimide
28 (cf. Scheme 4a). The reaction is Friedel–Crafts-like and
General Procedure A: Synthesis of N,O-Acetals by Reaction
of N-Acyl Phthalimides with Aldehydes. Aldehyde (2 equiv)
was added to a mixture of N-acyl phthalimide (1 equiv),
potassium phthalimide (20 mg, 0.11 mmol, 0.2 equiv), NaI (16
mg, 0.11 mmol, 0.2 equiv), 4Å MS (100 mg), MeCN (0.53 mL),
and EtOAc (0.53 mL) at room temperature with stirring. After 24
h, the mixture was diluted in Et2O, and sequentially washed with
sat. aq. NH4Cl (1x), 1 M aq. NaOH (3x), and brine (1x). The
organic phase was dried (MgSO4) and concentrated. The crude
material was purified by normal phase flash chromatography
using a mixture of hexanes/EtOAc eluent.
presumably proceeds through
a
highly electrophilic
phthalimidoyl iminium ion.5c,8c Subsequent phthalimide removal
in the presence of hydrazine affords α-branched benzylic amine
29, which is a known19 precursor to cetirizine, the active
ingredient in Zyrtec. Similarly, N,O-acetal 8n was treated with
TiCl4 to induce an intramolecular Friedel–Crafts reaction to give
30. In this case, subsequent phthalimide removal would form 1-
aminoindan (31), a precursor to rasagiline, the active ingredient
in Azilect.20 These results demonstrate the potential utility of the
N,O-acetals prepared under the reported conditions. Namely,
using this approach, a number of α-branched aryl amines, a
General Procedure B: Synthesis of N,O-Acetals by Reaction
of N-Acyl Phthalimides with Electron Rich Aldehydes.
Aldehyde (2 equiv) was added to a mixture of N-acyl phthalimide

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Tetrahedron
(1 equiv), potassium phthalimide (100 mg, 0.54 mmol, 1
procedure (see above), and was in good agreement with
equiv), NaI (80 mg, 0.53, 1 equiv), 4Å MS (100 mg), MeCN
(0.53 mL), and EtOAc (0.53 mL) at room temperature with
stirring. After 24 h, the mixture was diluted in Et2O, and
sequentially washed with sat. aq. NH4Cl (1x), 1 M aq. NaOH
(3x), and brine (1x). The organic phase was dried (MgSO4) and
concentrated. The crude material was purified by normal phase
previously reported characterization results.8g
(1,3-Dioxoisoindolin-2-yl)(phenyl)methyl Acetate (8b). N,O-
Acetal 8b was prepared according to General Procedure A from 7
(102 mg, 0.54 mmol) and benzaldehyde (108 µL, 1.1 mmol).
Purification by gradient flash chromatography (SiO2,
hexanes:EtOAc 9:1 to 4:1) gave 8b (119 mg, 0.40 mmol, 74%).
1H NMR (300 MHz, CDCl3): δ 7.85 (nfom, 2H), 7.73 (nfom,
2H), 7.69 (s, 1H), 7.53–7.59 (m, 2H), 7.33–7.43 (m, 3H), and
2.21 (s, 3H). The 1H NMR data is in good agreement with
previously reported characterization results.8g
gradient flash chromatography using
hexanes/EtOAc eluent.
a
mixture of
General Procedure C: One-Pot Synthesis of N,O-Acetals from
Potassium Phthalimide and an Acid Chloride. Acid chloride
(1 equiv) was added to a mixture of isobutyraldehyde (110 µL,
1.2 mmol, 2.2 equiv), potassium phthalimide (200 mg, 1.1 mmol,
2 equiv), NaI (160 mg, 1.1 mmol, 2 equiv), 4Å MS (100 mg),
MeCN (0.53 mL), and EtOAc (0.53 mL) at room temperature
with stirring. After 24 h, the mixture was diluted in Et2O, and
sequentially washed with sat. aq. NH4Cl (1x), 1 M aq. NaOH
(3x), and brine (1x). The organic phase was dried (MgSO4) and
concentrated. The crude material was purified by normal phase
(1,3-Dioxoisoindolin-2-yl)methyl Acetate (8c). N,O-Acetal 7 was
prepared according to General Procedure A from 8c (91 mg, 0.48
mmol) and paraformaldehyde (72 mg). Purification by flash
chromatography (SiO2, hexanes:EtOAc 4:1) gave 8c (40 mg, 0.18
mmol, 38%). H NMR (300 MHz, CDCl3): δ 7.94 (nfom, 2H),
7.79 (nfom, 2H), 5.72 (s, 2H), and 2.21 (s, 3H). The H NMR
1
1
data is in good agreement with previously reported
characterization results.8g
gradient flash chromatography using
hexanes/EtOAc eluent.
a
mixture of
1-(1,3-Dioxoisoindolin-2-yl)ethyl Acetate (8d). N,O-Acetal 8d
was prepared according to General Procedure A from 7 (98 mg,
0.52 mmol) and 4 equivalents of acetaldehyde (0.1 mL, 2 mmol).
Purification by flash chromatography (SiO2, hexanes:EtOAc 4:1)
gave 8d (101 mg, 0.43 mmol, 83%). 1H NMR (300 MHz,
CDCl3): δ 7.89 (nfom, 2H), 7.77 (nfom, 2H), 6.75 (q, J = 6.5 Hz,
General Procedure D: One-Pot Synthesis of N,O-Acetals from
an Amine and an Acid Chloride. Benzoyl chloride (1 equiv)
was added to a mixture of isobutyraldehyde (100 µL, 1.1 mmol, 2
equiv), amine (1.5–2 equiv), NaI (160 mg, 1.1 mmol, 2 equiv),
triethylamine (150 µL, 1.1 mmol, 1 equiv), 4Å MS (100 mg),
MeCN (0.53 mL, 1 M), and EtOAc (0.53 mL, 1 M) at room
temperature with stirring. After 24 h, the mixture was diluted in
Et2O, and sequentially washed 1 M aq. NaOH (3x) and brine
(1x). The organic phase was dried (MgSO4) and concentrated.
1
1H), 2.08 (s, 3H), and 1.86 (d, J = 6.4 Hz, 3H). The H NMR
data is in good agreement with previously reported
characterization results.8g
1-(1,3-Dioxoisoindolin-2-yl)butyl Acetate (8e). N,O-Acetal 8e
was prepared according to General Procedure A from 7 (101 mg,
0.53 mmol) and butyraldehyde (96 µL, 1.1 mmol). Purification
by flash chromatography (SiO2, hexanes:EtOAc 4:1) gave 8e
(116 mg, 0.44 mmol, 83%). H NMR (300 MHz, CDCl3): δ 7.88
(nfom, 2H), 7.75 (nfom, 2H), 6.62 (t, J = 7.5 Hz, 1H), 2.11–2.37
(m, 2H), 2.08 (s, 3H), 1.30–1.49 (m, 2H), and 0.97 (t, J = 7.3 Hz,
2-Acetylisoindoline-1,3-dione (7). Acetic anhydride (52.2 mL,
0.553 mol) was added to a mixture of potassium phthalimide
(51.2 g, 0.276 mol) and acetonitrile (350 mL) at room
temperature and with stirring. After 24 h, the mixture was diluted
in EtOAc and washed with sat. aq. NaHCO3 and brine. The
organic phase was dried (MgSO4) and concentrated. The
resulting solid was recrystallized from EtOAc to give known 7 as
an off-white solid (45.6 g, 0.241 mol, 87%). 1H NMR (300 MHz,
CDCl3): δ 7.99 (nfom, 2H), 7.86 (nfom, 2H), and 2.69 (s, 3H). 1H
NMR data for 7 was in good agreement with those described
previously.21
1
1
3H). The H NMR data is in good agreement with previously
reported characterization results.8g
1-(1,3-Dioxoisoindolin-2-yl)heptyl Acetate (8f). N,O-Acetal 8f
was prepared according to General Procedure A from 7 (101 mg,
0.53 mmol) and heptanal (151 µL, 1.1 mmol). Purification by
gradient flash chromatography (SiO2, pure hexanes to
hexanes:EtOAc 6:1) gave 8f (118 mg, 0.39 mmol, 74%) as a
1-(1,3-Dioxoisoindolin-2-yl)-2-methylpropyl
Acetate
(8a).
Isobutyraldehyde (9.5 mL, 104 mmol) was added to a mixture of
7 (10.74 g, 56.8 mmol), potassium phthalimide (1.97 g, 10.6
mmol), NaI (1.64 g, 10.9 mmol), 4Å MS (1.12 g), acetonitrile (50
mL), and ethyl acetate (50 mL) at room temperature and with
stirring. After 24 h, the mixture was diluted in Et2O, and
sequentially washed with sat. aq. NH4Cl (1x) and 1 M aq. NaOH
(3x). The resulting organic phase was dried (MgSO4) and
concentrated. The crude material was purified by flash
chromatography (SiO2, hexanes:EtOAc 4:1) to give 8a (11.73 g,
1
colorless oil. H NMR (300 MHz, CDCl3): δ 7.89 (nfom, 2H),
7.77 (nfom, 2H), 6.61 (dd, J = 7.0, 8.1 Hz, 1H), 2.12–2.40 (m,
2H), 2.09 (s, 3H), 1.14–1.44 (m, 8H), and 0.86 (t, J = 6.7 Hz,
3H). 13C NMR (75 MHz, CDCl3): δ 169.6, 166.9, 134.5, 131.5,
123.8, 74.9, 31.6, 31.2, 28.6, 24.9, 22.5, 20.9, and 14.1. IR (neat):
2957, 2930, 2860, 1781, 1752, 1723, 1469, 1376, 1223, 1022,
and 722 cm-1. HRMS: Calcd for C17H21NNaO4+ [M+Na+] requires
326.1363; found 326.1363.
1
44.9 mmol, 79%). H NMR (300 MHz, CDCl3): δ 7.88 (nfom,
2H), 7.76 (nfom, 2H), 6.22 (d, J = 10.5 Hz, 1H), 2.82–2.99
(nfom, 1H), 2.10 (s, 3H), 1.08 (d, J = 6.7 Hz, 3H), and 0.89 (d, J
1-(1,3-Dioxoisoindolin-2-yl)-2,2-dimethylpropyl Acetate (8g).
N,O-Acetal 8g was prepared according to General Procedure A
from 7 (103 mg, 0.54 mmol) and trimethylacetaldehyde (116 µL,
1.1 mmol). Purification by flash chromatography (SiO2,
hexanes:EtOAc 4:1) gave 8g (117 mg, 0.43 mmol, 80%) as a
white solid. 1H NMR (300 MHz, CDCl3): δ 7.85 (nfom, 2H),
7.74 (nfom, 2H), 6.23 (s, 1H), 2.12 (s, 3H), and 1.10 (s, 9H). 13C
NMR (75 MHz, CDCl3): δ 170.0, 167.3, 134.3, 131.6, 123.6,
82.3, 36.7, 26.0, and 20.5. IR (neat): 2967, 2912, 2874, 1777,
1746, 1720, 1612, 1370, 1354, 1234, 1217, 1122, 1052, 1038,
1
= 6.8 Hz, 3H). The H NMR data is in good agreement with
previously reported characterization results.8g
One
Pot
Synthesis
of
1-(1,3-Dioxoisoindolin-2-yl)-2-
methylpropyl Acetate (8a). N,O-Acetal 8a was prepared
according to General Procedure C with acetyl chloride (38 µL,
0.53 mmol). Purification by flash chromatography (SiO2,
hexanes:EtOAc 4:1) gave 8a (79 mg, 0.30 mmol, 57%). The H
NMR data matched that obtained using the aforementioned
1
and 1024 cm-1. HRMS: Calcd for C15H17NNaO4 [M+Na+]
+
requires 298.1050; found 298.1053. MP: 87–89 ºC.

ACCEPTED MANUSCRIPT
7
1-(1,3-Dioxoisoindolin-2-yl)-3-methylbutyl Acetate (8h). N,O-
Acetal 8h was prepared according to General Procedure A from 7
(103 mg, 0.54 mmol) and isovaleraldehyde (117 µL, 1.1 mmol).
Purification by flash chromatography (SiO2, hexanes:EtOAc 4:1)
gave 8h (115 mg, 0.42 mmol, 78%). 1H NMR (300 MHz,
CDCl3): δ 7.89 (nfom, 2H), 7.77 (nfom, 2H), 6.71 (dd, J = 6.9,
8.1 Hz, 1H), 2.21–2.33 (nfom, 1H), 2.08 (s, 3H), 2.00–2.14
(nfom, 1H), 1.69–1.53 (nfom, 1H), 0.99 (d, J = 6.8 Hz, 3H), and
0.96 (d, J = 6.7 Hz, 3H). The 1H NMR data is in good agreement
with previously reported characterization results.8g
mixture of diastereomers): δ 7.85–7.93 (m, 2H), 7.74–7.82 (m,
2H), 6.68–6.77 (m, 1H), 2.48–2.61 (m, 1H, one diastereomer),
2.25–2.38 (m, 1H, one diastereomer), 2.079 (s, 3H, one
diastereomer), 2.075 (s, 3H, one diastereomer), 1.76–2.14 (m,
3H), 1.07–1.61 (m, 5H), 1.21 (s, 3H), 1.189 (s, 3H, one
diastereomer), 1.182 (s, 3H, one diastereomer), 0.98 (d, J = 6.5
Hz, 3H, one diastereomer), and 0.96 (d, J = 6.6 Hz, 3H, one
diastereomer). 13C NMR (75 MHz, CDCl3, mixture of
diastereomers): δ 169.7, 169.6, 166.94, 166.86, 134.51, 134.48,
131.5, 123.78, 123.75, 73.8, 73.5, 70.93, 70.89, 44.0, 43.8, 38.2,
37.6, 37.4, 36.8, 29.33, 29.31, 29.2, 29.1, 21.34, 21.26, 20.94,
20.89, 19.38, and 19.32. IR (neat): 3487 (br), 2967, 2938, 1781,
1751, 1723, 1468, 1375, 1225, 1020, and 723 cm-1. HRMS:
Cyclopropyl(1,3-dioxoisoindolin-2-yl)methyl Acetate (8i). N,O-
Acetal 8i was prepared according to General Procedure A from 7
(93 mg, 0.49 mmol) and cyclopropanecarboxaldehyde (73 µL,
0.98 mmol). Purification by flash chromatography (SiO2,
hexanes:EtOAc 4:1) gave 8i (87 mg, 0.34 mmol, 69%) as a white
solid. 1H NMR (300 MHz, CDCl3): δ 7.90 (nfom, 2H), 7.77
(nfom, 2H), 5.85 (d, J = 9.7 Hz, 1H), 2.11 (s, 3H), 2.08–2.22 (m,
1H), 0.53–0.82 (m, 3H), and 0.42 (nfom, 1H). 13C NMR (75
MHz, CDCl3): δ 169.5, 166.7, 134.4, 131.6, 123.8, 78.5, 20.9,
13.0, 4.8, and 2.5. IR (neat): 3007, 1780, 1761, 1742, 1720, 1468,
1377, 1226, 1103, 1015, 975, and 717 cm-1. HRMS: Calcd for
+
Calcd for C20H27NNaO5 [M+Na+] requires 384.1781; found
384.1781.
1-(1,3-Dioxoisoindolin-2-yl)-2-phenylethyl
Acetate
(8m).
Phenylacetaldehyde (125 µL, 1.1 mmol) was added to a mixture
of 7 (101 mg, 0.53 mmol), triethylamine (74 µL, 0.53 mmol),
potassium phthalimide (20 mg, 0.11 mmol), NaI (16 mg, 0.11
mmol), 4Å MS (100 mg), MeCN (0.53 mL), and EtOAc (0.53
mL) at room temperature and with stirring. After 24 h, the
mixture was diluted in Et2O, and sequentially washed with sat.
aq. NH4Cl (1x) and 1 M aq. NaOH (3x). The resulting organic
phase was dried (MgSO4) and concentrated. The crude material
was purified by gradient flash chromatography (SiO2,
hexanes:EtOAc 9:1 to 4:1) to give 8m (83 mg, 0.27 mmol, 51%).
1H NMR (300 MHz, CDCl3): δ 7.81(nfom, 2H), 7.69 (nfom, 2H),
7.14–7.29 (m, 5H), 6.83 (dd, J = 6.7, 8.7 Hz, 1H), 3.66 (dd, J =
8.7, 13.7 Hz, 1H), 3.52 (dd, J = 6.6, 13.8 Hz, 1H), and 2.05 (s,
+
C14H13NNaO4 [M+Na+] requires 282.0737; found 282.0738.
MP: 126–131 ºC.
Cyclohexyl(1,3-dioxoisoindolin-2-yl)methyl Acetate (8j). N,O-
Acetal 8j was prepared according to General Procedure A from 7
(102 mg, 0.54 mmol) and cyclohexanecarboxaldehyde (129 µL,
1.1 mmol). Purification by flash chromatography (SiO2,
hexanes:EtOAc 6:1) gave 8j (139 mg, 0.46 mmol, 85%) as white
solid. 1H NMR (300 MHz, CDCl3): δ 7.88 (nfom, 2H), 7.76
(nfom, 2H), 6.32 (d, J = 10.5 Hz, 1H), 2.59 (qt, J = 11, 3.7 Hz,
1H), 2.10 (s, 3H), 1.87–2.02 (nfom, 1H), 1.59–1.85 (m, 3H),
1.40–1.54 (nfom, 1H), and 0.94–1.39 (m, 5H). 13C NMR (75
MHz, CDCl3): δ 169.8, 166.9, 134.4, 131.4, 123.7, 78.1, 37.9,
29.2, 27.9, 25.9, 25.2, 25.1, and 20.7. IR (neat): 2930, 2854,
1780, 1758, 1721, 1363, 1222, 1022, 870, and 721 cm-1. HRMS:
1
3H). The H NMR data is in good agreement with previously
reported characterization results.8g
1-(1,3-Dioxoisoindolin-2-yl)-3-phenylpropyl
Acetate
(8n).
Hydrocinnamaldehyde (1.41 mL, 10.7 mmol) was added to a
mixture of N-acetyl phthalimide (7, 1.10 g, 5.82 mmol),
potassium phthalimide (0.21 g, 1.1 mmol), NaI (0.16 g, 1.1
mmol), 4Å MS (0.20 g), acetonitrile (5.3 mL), and ethyl acetate
(5.3 mL) at room temperature and with stirring. After 24 h, the
mixture was diluted in Et2O, and sequentially washed with sat.
aq. NH4Cl (1x) and 1 M aq. NaOH (3x). The resulting organic
phase was dried (MgSO4) and concentrated. The crude material
was purified by gradient flash chromatography (pure hexanes to
6:1 hexanes:EtOAc to 4:1 hexanes:EtOAc) to give 8n (1.47 g,
+
Calcd for C17H19NNaO4 [M+Na+] requires 324.1206; found
324.1209. MP: 110–112 ºC.
1-(1,3-Dioxoisoindolin-2-yl)-3,7-dimethyloct-6-en-1-yl Acetate
(8k). N,O-Acetal 8k was prepared according to General
Procedure A from 7 (103 mg, 0.54 mmol) and (±)-citronellal
(194 µL, 1.1 mmol). Purification by flash chromatography (SiO2,
hexanes:EtOAc 6:1) gave 8k (141 mg, 0.41 mmol, 76%) as a
mixture of two diastereomers that formed a colorless oil. 1H
NMR (300 MHz, CDCl3, ~1:1 mixture of two diastereomers): δ
7.83–7.91 (m, 2H), 7.71–7.78 (m, 2H), 6.66–6.75 (m, 1H), 4.95–
5.05 (m, 1H), 2.49 (ddd, J = 4.2, 9.2, 13.5 Hz, 1H, one
diastereomer), 2.31 (nfom, 1H, one diastereomer), 2.07 (s, 3H),
1.83–2.1 (m, 4H), 1.59 (s, 3H, one diastereomer), 1.573 (s, 3H,
one diastereomer), 1.568 (s, 3H, one diastereomer), 1.54 (s, 3H,
one diastereomer), 1.14–1.70 (m, 2H), 0.97 (d, J = 6.4 Hz, 3H,
1
4.55 mmol, 78%) as a white solid. H NMR (300 MHz, CDCl3):
δ 7.83 (nfom, 2H), 7.72 (nfom, 2H), 7.11–7.23 (m, 4H), 7.07
(nfom, 1H), 6.65 (br t, J = 6.4 Hz, 1H), 2.48–2.84 (m, 4H), and
2.06 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 169.5, 166.8, 139.9,
134.4, 131.4, 128.4, 128.3, 126.1, 123.6, 74.5, 32.4, 31.4, and
20.8. IR (neat): 3088, 3063, 3028, 2936, 2865, 1781, 1753, 1722,
1604, 1496, 1468, 1454, 1376, 1359, 1222, 1024, 721, and 700
cm-1. HRMS: Calcd for C19H17NNaO4 [M+Na+] requires
+
346.1050; found 346.1053. MP: 80–82 ºC.
one diastereomer), and 0.93 (d,
J = 6.5 Hz, 3H, one
diastereomer). 13C NMR (75 MHz, CDCl3, mixture of two
diastereomers): δ 169.70, 169.66, 166.96, 166.92, 134.5, 131.69,
131.63, 124.36, 124.33, 123.8, 73.9, 73.5, 38.3, 37.8, 37.1, 36.3,
29.2, 28.9, 25.7, 25.3, 25.1, 21.01, 20.97, 19.4, and 17.7. IR
(neat): 2963, 2929, 2876, 1781, 1753, 1723, 1468, 1376, 1224,
(1,3-Dioxoisoindolin-2-yl)(p-tolyl)methyl Acetate (8o). N,O-
Acetal 8o was prepared according to General Procedure A from 7
(99 mg, 0.52 mmol) and p-tolualdehyde (126 µL, 1.1 mmol).
Purification by gradient flash chromatography (SiO2,
hexanes:EtOAc 9:1 to 4:1) gave 8o (106 mg, 0.34 mmol, 65%) as
1020, 976, and 872 cm-1. HRMS: Calcd for C20H25NNaO4
a white solid. H NMR (300 MHz, CDCl3): δ 7.85 (nfom, 2H),
+
1
[M+Na+] requires 366.1676; found 366.1674.
7.73 (nfom, 2H), 7.65 (s, 1H), 7.45 (d, J = 8.1 Hz, 2H), 7.19 (d, J
= 8.0 Hz, 2H), 2.34 (s, 3H), and 2.20 (s, 3H). 13C NMR (75 MHz,
CDCl3): δ 169.4, 166.4, 138.9, 134.5, 132.2, 131.7, 129.2, 126.4,
123.8, 74.3, 21.3, and 20.9. IR (neat): 3031, 2953, 2924, 2865,
1780, 1760, 1747, 1727, 1613, 1517, 1468, 1376, 1356, 1332,
1223, 1031, 1020, 738, and 720 cm-1. HRMS: Calcd for
1-(1,3-Dioxoisoindolin-2-yl)-7-hydroxy-3,7-dimethyloctyl Acetate
(8l). N,O-Acetal 8l was prepared according to General Procedure
A from 7 (102 mg, 0.54 mmol) and (±)-7-hydroxycitronellal (190
mg, 1.1 mmol). Purification by gradient flash chromatography
(SiO2, hexanes:EtOAc 6:1 to 4:1 to 1:1) gave 8l (129 mg, 0.36
mmol, 67%) colorless oil. 1H NMR (300 MHz, CDCl3, ~1:1

ACCEPTED MANUSCRIPT
8
Tetrahedron
+
C18H15NNaO4 [M+Na+] requires 332.0893; found 332.0869.
mmol, 85%) as a white solid. 1H NMR (300 MHz, CDCl3): δ
7.87 (nfom, 2H), 7.75 (nfom, 2H), 7.62 (s, 1H), 7.52 (d, J = 8.6
Hz, 2H), 7.44 (d, J = 8.6 Hz, 2H), and 2.21 (s, 3H) as a white
solid. 13C NMR (75 MHz, CDCl3): δ 169.2, 166.3, 134.7, 134.2,
131.8, 131.6, 128.3, 124.0, 123.2, 73.7, and 20.9. IR (neat): 3062,
1781, 1763, 1746, 1727, 1377, 1356, 1332, 1219, 1030, 1012,
MP: 132–137 ºC.
(1,3-Dioxoisoindolin-2-yl)(2-nitrophenyl)methyl Acetate (8p).
N,O-Acetal 8p was prepared according to General Procedure A
from 7 (101 mg, 0.53 mmol) and 2-nitrobenzaldehyde (165 mg,
1.1 mmol). Purification by gradient flash chromatography (SiO2,
pure hexanes to hexanes:EtOAc 6:1 to 4:1) gave 8p (161 mg,
740, and 722 cm-1. HRMS: Calcd for C17H12BrNNaO4
+
[M(79Br)+Na+] requires 395.9842; found 395.9847. MP: 172–174
ºC.
1
0.47 mmol, 89%) as a white solid. H NMR (300 MHz, CDCl3):
δ 8.21 (s, 1H), 8.06 (dd, J = 1.1, 8.1 Hz, 1H), 7.98 (d, J = 7.9 Hz,
1H), 7.86 (nfom, 2H), 7.77 (nfom, 2H), 7.74 (dt, J = 1.5, 7.8 Hz,
1H), 7.52 (dt, J = 1.6, 7.9 Hz, 1H), and 2.20 (s, 3H). 13C NMR
(75 MHz, CDCl3): δ 168.6, 166.1, 147.2, 134.7, 133.2, 131.2,
130.1, 129.7, 129.6, 125.2, 123.9, 71.0, and 20.6. IR (neat): 1784,
1761, 1729, 1530, 1380, 1352, 1218, 1023, and 721 cm-1. HRMS:
(1,3-Dioxoisoindolin-2-yl)(pyridin-3-yl)methyl Acetate (8u).
N,O-Acetal 8u was prepared according to General Procedure A
from 7 (102 mg, 0.54 mmol) and 3-pyridinecarboxaldehyde (100
µL, 1.1 mmol). Purification by gradient flash chromatography
(SiO2, CH2Cl2:EtOH 98:2 for ca. six column volumes then
hexanes:EtOAc:Et3N 50:45:5 for ca. 10 column volumes) gave
Calcd for C17H12N2NaO6 [M+Na+] requires 363.0588; found
+
1
363.0610. MP: 150–153 ºC.
8u (113 mg, 0.38 mmol, 70%) as an oily solid. H NMR (300
MHz, CDCl3, referenced to TMS): δ 8.79 (d, J = 1.8 Hz, 1H),
8.61 (dd, J = 1.4, 4.8 Hz, 1H), 7.97 (br d, J = 8.0 Hz, 1H), 7.88
(nfom, 2H), 7.77 (nfom, 2H), 7.72 (s, 1H), 7.36 (dd, J = 4.6, 8.0
Hz, 1H), and 2.23 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 169.0,
166.1, 150.1, 147.9, 134.7, 134.5, 131.3, 131.0, 123.9, 123.2,
72.3, and 20.7. IR (neat): 3188, 3060, 2960, 2920, 2850, 1774,
1732, 1730, 1606, 1469, 1309, and 1054 cm-1. HRMS: Calcd for
C16H13N2O4+ [M+H+] requires 297.0870; found 297.0869.
(1,3-Dioxoisoindolin-2-yl)(4-nitrophenyl)methyl Acetate (8q).
N,O-Acetal 8q was prepared according to General Procedure A
from 7 (99 mg, 0.52 mmol) and 4-nitrobenzaldehyde (161 mg,
1.1 mmol). Purification by gradient flash chromatography (SiO2,
pure hexanes to hexanes:EtOAc 6:1 to 4:1) gave 8q (144 mg,
1
0.42 mmol, 81%) as a white solid. H NMR (300 MHz, CDCl3):
δ 8.25 (d, J = 8.9 Hz, 2H), 7.88 (nfom, 2H), 7.78 (nfom, 2H),
7.731 (d, J = 8.6 Hz, 2H), 7.729 (s, 1H), and 2.25 (s, 3H). 13C
NMR (75 MHz, CDCl3): δ 169.0, 166.1, 148.2, 142.0, 134.9,
131.4, 127.6, 124.1, 123.8, 72.9, and 20.8. IR (neat): 3108, 3080,
2849, 2777, 2732, 1781, 1765, 1709, 1680, 1526, 1382, 1347,
1324, 1199, 1109, 850, 815, 740, and 722 cm-1. HRMS: Calcd for
(1,3-Dioxoisoindolin-2-yl)(furan-2-yl)methyl Acetate (8v). N,O-
Acetal 8v was prepared according to General Procedure A from 7
(104 mg, 0.55 mmol) and 2-furaldehyde (88 µL, 1.1 mmol).
Purification by gradient flash chromatography (SiO2, pure
hexanes to hexanes:EtOAc 6:1 to 4:1) gave 8v (86 mg, 0.30
mmol, 55%) as a golden yellow solid. 1H NMR (300 MHz,
CDCl3): δ 7.91 (nfom, 2H), 7.77 (nfom, 2H), 7.70 (s, 1H), 7.40
(dd, J = 0.9, 2.0 Hz, 1H), 6.58 (br d, J = 3.4 Hz, 1H), 6.41 (dd, J
= 1.9, 3.5 Hz, 1H), and 2.18 (s, 3H). 13C NMR (75 MHz, CDCl3):
δ 169.1, 166.1, 147.4, 143.1, 134.7, 131.7, 124.1, 110.8, 109.6,
68.8, and 20.8. IR (neat): 3150, 3129, 2944, 1783, 1760, 1729,
1611, 1504, 1469, 1376, 1357, 1335, 1216, 1031, 1015, and 717
+
C17H12N2NaO6 [M+Na+] requires 363.0588; found 363.0601.
MP: 104–107 ºC.
(2-Chlorophenyl)(1,3-dioxoisoindolin-2-yl)methyl Acetate (8r).
N,O-Acetal 8r was prepared according to General Procedure A
from 7 (100 mg, 0.53 mmol) and 2-chlorobenzaldehyde (120 µL,
1.1 mmol). Purification by gradient flash chromatography (SiO2,
pure hexanes to hexanes:EtOAc 6:1 to 4:1) gave 8r (114 mg,
1
0.35 mmol, 66%) as a white solid. H NMR (300 MHz, CDCl3):
+
cm-1. HRMS: Calcd for C15H11NNaO5 [M+Na+] requires
δ 7.91 (br d, J = 8.1 Hz, 1H), 7.87 (s, 1H), 7.85 (nfom, 2H), 7.74
(nfom, 2H), 7.25–7.42 (m, 3H), and 2.22 (s, 3H). 13C NMR (75
MHz, CDCl3): δ 168.7, 166.1, 134.6, 132.2, 131.4, 130.3, 129.7,
129.3, 126.5, 123.9, 71.7, and 20.8. IR (neat): 3072, 2962, 1781,
1766, 1749, 1728, 1459, 1445, 1379, 1351, 1333, 1217, 1023,
308.0529; found 308.0533. MP: 116–120 ºC.
(1,3-Dioxoisoindolin-2-yl)(4-methoxyphenyl)methyl
(8w). N,O-Acetal 8w was prepared according to General
Procedure from (93 mg, 0.49 mmol) and 4-
Acetate
B
7
+
and 722 cm-1. HRMS: Calcd for C17H12ClNNaO4 [M+Na+]
methoxybenzaldehyde (131 µL, 1.1 mmol). Purification by
gradient flash chromatography (SiO2, pure hexanes to
hexanes:EtOAc 6:1 to 4:1) gave 8w (69 mg, 0.21 mmol, 43%) a
white solid. 1H NMR (300 MHz, CDCl3): δ 7.85 (nfom, 2H),
7.73 (nfom, 2H), 7.62 (s, 1H), 7.52 (d, J = 8.8 Hz, 2H), 6.90 (d, J
= 8.7 Hz, 2H), 3.79 (s, 3H), and 2.20 (s, 3H). 13C NMR (75 MHz,
CDCl3): δ 169.3, 166.4, 160.0, 134.5, 131.6, 128.0, 127.2, 123.8,
113.8, 74.3, 55.4, and 20.9. IR (neat): 2961, 2937, 1749, 1726,
1614, 1516, 1376, 1362, 1354, 1253, 1222, 1031, and 734 cm-1.
requires 352.0347; found 352.0350. MP: 137–142 ºC.
(4-Chlorophenyl)(1,3-dioxoisoindolin-2-yl)methyl Acetate (8s).
4-Chlorobenzaldehyde (1.53 g, 11 mmol) was added to a mixture
of N-acetyl phthalimide (7, 1.01 g, 5.34 mmol), potassium
phthalimide (0.20 g, 1.1 mmol), NaI (0.16 g, 1.1 mmol), 4Å MS
(0.20 g), acetonitrile (5.3 mL), and ethyl acetate (5.3 mL) at room
temperature and with stirring. After 24 h, the mixture was diluted
in Et2O, and sequentially washed with sat. aq. NH4Cl (1x) and 1
M aq. NaOH (3x). The resulting organic phase was dried
(MgSO4) and concentrated. The crude material was purified by
gradient flash chromatography (SiO2, pure hexanes to
hexanes:EtOAc 6:1 to 4:1) to give 8s (1.37 g, 4.15 mmol, 78%).
1H NMR (300 MHz, CDCl3): δ 7.87 (nfom, 2H), 7.76 (nfom,
2H), 7.64 (s, 1H), 7.51 (br d, J = 8.5 Hz, 2H), 7.36 (br d, J = 8.5
Hz, 2H), and 2.21 (s, 3H). The 1H NMR data is in good
agreement with previously reported characterization results.8g
+
HRMS (ESI-TOF): Calcd for C18H15NNaO5 [M+Na+] requires
348.0842; found 348.0859. MP: 84–89 ºC.
(3,4-Dimethoxyphenyl)(1,3-dioxoisoindolin-2-yl)methyl Acetate
(8x). N,O-Acetal 8x was prepared according to General
Procedure
B from 7 (100 mg, 0.53 mmol) and 3,4-
dimethoxybenzaldehyde (176 mg, 1.1 mmol). Purification by
gradient flash chromatography (SiO2, pure hexanes to
hexanes:EtOAc 6:1 to 4:1) gave 8x (62 mg, 0.17 mmol, 32%). 1H
NMR (300 MHz, CDCl3): δ 7.86 (nfom, 2H), 7.74 (nfom, 2H),
7.59 (s, 1H), 7.14–7.20 (m 2H), 6.86 (d, J = 8.0 Hz, 1H), 3.91 (s,
3H), 3.87 (s, 3H), and 2.20 (s, 3H). 13C NMR (75 MHz, CDCl3):
δ 169.4, 166.5, 149.6, 149.0, 134.6, 131.7, 127.6, 123.9, 119.5,
110.8, 110.1, 74.7, 56.1, 56.0, and 21.0. IR (neat): 3005, 2960,
2939, 2839, 1780, 1756, 1723, 1519, 1375, 1356, 1331, 1266,
(4-Bromophenyl)(1,3-dioxoisoindolin-2-yl)methyl Acetate (8t).
N,O-Acetal 8t was prepared according to General Procedure A
from 7 (104 mg, 0.55 mmol) and 4-bromobenzaldehyde (198 mg,
1.1 mmol). Purification by gradient flash chromatography (SiO2,
pure hexanes to hexanes:EtOAc 6:1 to 4:1) gave 8t (175 mg, 0.47

ACCEPTED MANUSCRIPT
9
1220 1161, 1144, 1119, 1027, 916, 737, and 718 cm-1. HRMS
1750, 1711, 1612, 1364, 1309, 1109, 1047, and 738 cm-1.
(ESI-TOF): Calcd for C19H17NNaO6 [M+Na+] requires
HRMS: Calcd for C14H15NNaO3 [M+Na+] requires 268.0944;
+
+
378.0948; found 378.0947.
found 268.0945. MP: 180–186 ºC.
(1,3-Dioxoisoindolin-2-yl)(1-(2-methylallyl)-1H-indol-2-
1-(1,3-Dioxoisoindolin-2-yl)-2-methylpropyl Benzoate (11). N,O-
Acetal 11 was prepared according to General Procedure C with
benzoyl chloride (62 µL, 0.53 mmol). Purification by flash
chromatography (SiO2, hexanes:EtOAc 4:1) gave 11 (149 mg,
yl)methyl Acetate (8y). N,O-Acetal 7 was prepared according to
General Procedure B from 7 (100 mg, 0.53 mmol) and 1-(2-
methylallyl)-1H-indole-2-carbaldehyde22 (213 mg, 1.1 mmol).
Purification by gradient flash chromatography (SiO2,
hexanes:EtOAc 6:1 to 4:1 to 2:1) gave 8y (84 mg, 0.22 mmol,
42%) as a pale yellow solid. 1H NMR (300 MHz, CDCl3): δ 7.86
(s, 1H), 7.84 (nfom, 2H), 7.73 (nfom, 2H), 7.64 (d, J = 7.8 Hz,
1H), 7.15–7.21 (m, J = 4.0 Hz, 2H), 7.07–7.15 (m, 1H), 6.97 (s,
1H), 4.65 (s, 2H), 4.44 (s, 1H), 4.02 (s, 1H), 2.21 (s, 3H), and
1.64 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 169.1, 166.1, 140.6,
137.7, 134.6, 132.3, 131.6, 127.0, 123.8, 122.7, 121.4, 120.2,
110.8, 109.7, 103.5, 68.6, 49.1, 20.9, and 19.9. IR (neat): 3060,
2940, 1780, 1759, 1725, 1462, 1373, 1217, 1034, and 715 cm-1.
1
0.46 mmol, 87%) as a white solid. H NMR (300 MHz, CDCl3):
δ 8.1 (br d, J = 7.5 Hz, 2H), 7.88 (nfom, 2H), 7.74 (nfom, 2H),
7.57 (br t, J = 7.5 Hz, 1H), 7.43 (br t, J = 7.8 Hz, 2H), 6.48 (d, J
= 10.4 Hz, 1H), 3.01–3.19 (m, 1H), 1.16 (d, J = 6.6 Hz, 3H), and
0.97 (d, J = 6.8 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 166.9,
165.3, 134.4, 133.5, 131.5, 130.0, 129.3, 128.5, 123.8, 79.8, 29.7,
19.1, and 18.0. IR (neat): 3064, 2970, 2877, 1781, 1733, 1601,
1469, 1452, 1371, 1252, 1090, 1064, 994, and 710 cm-1. HRMS:
+
Calcd for C19H17NNaO4 [M+Na+] requires 346.1050; found
346.1051. MP: 95–103 ºC.
+
HRMS: Calcd for C23H20N2NaO4 [M+Na+] requires 411.1315;
1-(1,3-Dioxoisoindolin-2-yl)-2-methylpropyl 3-Methylbutanoate
(12). N,O-Acetal 12 was prepared according to General
Procedure C with isovaleryl chloride (65 µL, 0.53 mmol).
Purification by flash chromatography (SiO2, hexanes:EtOAc 4:1)
found 411.1320. MP: 57–61 ºC.
(3,4-Dimethoxyphenyl)(1,3-dioxoisoindolin-2-yl)methyl Acetate
(8z). Phenyliodonium diacetate (PIDA, 240 mg, 0.75 mmol) was
added to a mixture of (+)-diethyl l-tartate (110 µL, 0.63 mmol)
and CH2Cl2 (1.1 mL) at room temperature and with stirring. After
1 h, N-acyl phthalimide 7 (100 mg, 0.53 mmol), NaI (16 mg, 0.11
mmol), potassium phthalimide (20 mg, 0.11), and triethylamine
(150 µL, 1.1 mmol) were sequentially added. After stirring
overnight, the mixture was diluted in EtOAc and sequentially
washed with sat. aq. NH4Cl (1x), 1 M aq. NaOH (3x), and brine.
The organic phase was dried (MgSO4) and concentrated. The
crude material was purified by gradient flash chromatography
(SiO2, pure hexanes to hexanes:EtOAc 6:1 to hexanes:EtOAc
1
gave 12 (147 mg, 0.49 mmol, 92%) as a clear oil. H NMR (300
MHz, CDCl3): δ 7.88 (nfom, 2H), 7.75 (nfom, 2H), 6.20 (d, J =
10.4 Hz, 1H), 2.80–2.99 (m, 1H), 2.23 (br d, J = 6.5 Hz, 2H),
2.00–2.17 (m, 1H), 1.08 (d, J = 6.6 Hz, 3H), 0.912 (d, J = 6.6 Hz,
3H), 0.907 (d, J = 6.6 Hz, 3H), and 0.89 (d, J = 6.7 Hz, 3H). 13C
NMR (75 MHz, CDCl3): δ 172.0, 167.0, 134.5, 131.5, 123.8,
79.3, 43.1, 29.5, 25.7, 22.4 (2xC), 19.1, and 18.0. IR (neat):
2964, 2931, 2875, 1783, 1749, 1724, 1469, 1372, 1164, 1087,
+
1015, and 721 cm-1. HRMS: Calcd for C17H21NaNO4 [M+Na+]
requires 326.1363; found 326.1366.
1
4:1) to give 8z (62 mg, 0.21 mmol, 40%) as a white solid. H
2-Methyl-1-(5-methyl-1,3-dioxoisoindolin-2-yl)propyl
3-
NMR (300 MHz, CDCl3): δ 7.95 (nfom, 2H), 7.73 (nfom, 2H),
6.98 (s, 1H), 4.31 (q, J = 7.1 Hz, 2H), 2.19 (s, 3H), and 1.28 (t, J
= 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 169.2, 166.0,
164.7, 134.7, 131.6, 124.3, 68.6, 63.2, 20.7, and 14.1. IR (neat):
2986, 1788, 1757, 1733, 1387, 1374, 1216, 1057, and 718 cm-1.
Methylbutanoate (13). Isolation and analytic data for 13,
observed in the crossover study, was obtained by independent
preparation using the following procedure. Isovaleryl chloride
(65 µL, 0.53 mmol) was added to
a mixture of 4-
methylphthalimide (200 mg, 1.2 mmol), isobutyraldehyde (108
µL, 1.19 mmol), NaI (170 mg, 1.1 mmol), 4Å MS (100 mg),
triethylamine (150 µL, 1.1 mmol), ethyl acetate (1.1 mL), and
acetonitrile (1.1 mL) at room temperature and with stirring. After
24 h, the mixture was diluted in EtOAc and washed with 1M
NaOH (3x) and brine. The organic phase was dried (MgSO4) and
concentrated. Purification by flash chromatography (SiO2,
hexanes:EtOAc 4:1) gave 13 (105 mg, 0.33 mmol, 62%) as a
+
HRMS: Calcd for C14H13NNaO6 [M+Na+] requires 314.0635;
found 314.0638. MP: 115–121 ºC.
2-Benzoylisoindoline-1,3-dione (N-Benzoyl Phthalimide, 9).
Benzoyl chloride (7.8 mL, 67 mmol) was added to a mixture of
potassium
phthalimide
(5.0
g,
27
mmol),
4-
dimethylaminopyridine (3.7 g, 30 mmol), and acetonitrile (34
mL) at room temperature and with stirring. After 24 h, the
mixture was gravity filtered and the solid residue was
recrystallized from a mixture of hexanes and EtOAc to give
1
white solid. H NMR (300 MHz, CDCl3): δ 7.76 (d, J = 7.6 Hz,
1H), 7.68 (s, 1H), 7.55 (d, J = 7.6 Hz, 1H), 6.19 (d, J = 10.4 Hz,
1H), 2.90 (nfom, 1H), 2.52 (s, 3H), 2.23 (d, J = 7.3 Hz, 2H), 2.09
(septet, J = 6.7 Hz, 1H), 1.08 (d, J = 6.6 Hz, 3H), 0.91 (d, J = 6.6
Hz, 3H), 0.90 (d, J = 7 Hz, 3H), and 0.88 (d, J = 7.6 Hz, 3H). 13C
NMR (75 MHz, CDCl3): δ 171.9, 167.1, 166.9, 145.8, 135.0,
131.8, 128.9, 124.2, 123.6, 79.1, 43.1, 29.5, 25.6, 22.3, 22.1,
19.0, and 17.9. IR (neat): 2963, 2875, 1779, 1748, 1721, 1618,
1468, 1430, 1363, 1101, and 1006 cm-1. HRMS (ESI-TOF):
1
known 9 as a white solid (4.51 g, 18.0 mmol, 67%). H NMR
(300 MHz, CDCl3): δ 8.00 (nfom, 2H), 7.84–7.91 (m, 4H), 7.64–
1
7.71 (m, 1H), and 7.48–7.55 (m, 2H). H NMR data for 9 was in
good agreement with those described previously.23
5-Methyl-2-(3-methylbutanoyl)isoindoline-1,3-dione
(10).
Isovaleryl chloride (0.50 mL, 4.1 mmol) was added to a mixture
of 4-methylphthalimide (0.78 g, 4.8 mmol), triethylamine (0.86
mL, 6.2 mmol), and acetonitrile (8.2 mL) at room temperature
and with stirring. After 24 h, the mixture was diluted in EtOAc
and washed with sat. aq. NaHCO3 and brine. The organic phase
was dried (MgSO4) and concentrated. The crude material was
purified by flash chromatography (SiO2, hexanes:EtOAc 4:1) to
+
Calcd for C18H23NNaO4 [M+Na+] requires 340.1519; found
340.1522. MP: 53–55 ºC.
2-Methyl-1-(5-methyl-1,3-dioxoisoindolin-2-yl)propyl Benzoate
(14). Isolation and analytic data for 14, observed in the crossover
study, was obtained by independent preparation using the
following procedure. Benzoyl chloride (62 µL, 0.54 mmol) was
added to a mixture of 4-methylphthalimide (200 mg, 1.2 mmol),
isobutyraldehyde (108 µL, 1.19 mmol), NaI (160 mg, 1.1 mmol),
4Å MS (100 mg), triethylamine (150 µL, 1.1 mmol), ethyl
acetate (1.1 mL), and acetonitrile (1.1 mL) at room temperature
and with stirring. After 24 h, the mixture was diluted in EtOAc
1
give 10 (713 mg, 2.91 mmol, 71%) as a white solid. H NMR
(300 MHz, CDCl3): δ 7.83 (d, J = 7.7 Hz, 1H), 7.74 (s, 1H), 7.65
(d, J = 7.6 Hz, 1H), 2.90 (d, J = 6.9 Hz, 2H), 2.57 (s, 3H), 2.25
(septet, J = 6.7 Hz, 1H), and 1.03 (d, J = 6.7 Hz, 6H). 13C NMR
(75 MHz, CDCl3): δ 171.6, 165.6, 165.5, 147.1, 136.2, 131.4,
128.5, 124.6, 124.3, 47.4, 25.0, 22.4, and 22.1. IR (neat): 2956,

ACCEPTED MANUSCRIPT
10
Tetrahedron
and washed with 1M NaOH (3x) and brine. The organic phase
1757, 1723, 1469, 1457, 1387, 1368, 1243, and 950 cm-1. HRMS:
+
was dried (MgSO4) and concentrated. Purification by flash
chromatography (SiO2, hexanes:EtOAc 6:1) gave 14 (145 mg,
0.43 mmol, 80%) as a yellow oil. 1H NMR (300 MHz, CDCl3): δ
8.09 (d, J = 7.7 Hz, 2H), 7.75 (d, J = 7.6 Hz, 1H), 7.67 (s, 1H),
7.50–7.60 (m, 2H), 7.43 (dd, J = 7.6, 7.8 Hz, 2H), 6.46 (d, J =
10.4 Hz, 1H), 3.09 (nfom, 1H), 2.50 (s, 3H), 1.15 (d, J = 6.7 Hz,
3H), and 0.96 (d, J = 6.8 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ
167.1, 167.0, 165.3, 145.8, 135.0, 133.5, 131.9, 130.0, 129.4,
128.9, 128.5, 124.2, 123.7, 79.7, 29.8, 22.1, 19.1, and 18.0. IR
(neat): 2965, 2938, 2874, 1780, 1748, 1720, 1469, 1373, 1359,
Calcd for C20H19NNaO5 [M+Na+] requires 376.1155; found
376.1156.
1-(1,3-Dioxoisoindolin-2-yl)-2-methylpropyl
4-Nitrobenzoate
(26e). N,O-Acetal 26e was prepared according to General
Procedure C with 4-nitrobenzoyl chloride (100 mg, 0.54 mmol).
Purification by flash chromatography (SiO2, hexanes:EtOAc 4:1)
1
gave 26e (172 mg, 0.47 mmol, 87%) as a white solid. H NMR
(300 MHz, CDCl3): δ 8.23–8.32 (m, 4H), 7.90 (nfom, 2H), 7.81
(nfom, 2H), 6.50 (d, J = 10.4 Hz, 1H), 3.03–3.21 (m, 1H), 1.17
(d, J = 6.6 Hz, 3H), and 0.99 (d, J = 6.8 Hz, 3H). 13C NMR (75
MHz, CDCl3): δ 166.8, 163.5, 150.8, 134.72, 134.66, 131.4,
131.2, 123.9, 123.7, 80.5, 29.7, 19.1, and 17.9. IR (neat): 3110,
3080, 3060, 2971, 2940, 2880, 1780, 1738, 1721, 1609, 1529,
1469, 1387, 1371, 1350, 1263, 1095, 938, and 718 cm-1. HRMS:
+
1223, and 720 cm-1. HRMS (ESI-TOF): Calcd for C20H19NNaO4
[M+Na+] requires 360.1206; found 360.1223.
1-(1,3-Dioxoisoindolin-2-yl)-2-methylpropyl Propionate (26a).
N,O-Acetal 26a was prepared according to General Procedure C
with propionyl chloride (48 µL, 0.55 mmol). Purification by flash
chromatography (SiO2, hexanes:EtOAc 6:1) gave 26a (129 mg,
Calcd for C19H16N2NaO6 [M+Na+] requires 391.0901; found
+
391.0898. MP: 137–139 ºC.
1
0.47 mmol, 85%) as a white solid. H NMR (300 MHz, CDCl3):
1-(1,3-Dioxoisoindolin-2-yl)-2-methylpropyl 3,5-Dinitrobenzoate
(26f). 3,5-Dinitrobenzoyl chloride (127 mg, 0.55 mmol) was
added to a mixture of isobutyraldehyde (110 µL, 1.2 mmol),
potassium phthalimide (200 mg, 1.1 mmol), NaI (160 mg, 1.1
mmol), 4Å MS (100 mg), MeCN (1 mL), and EtOAc (1 mL) at
room temperature and with stirring. After 24 h, the mixture was
diluted in Et2O, and sequentially washed with sat. aq. NH4Cl (1x)
and 1 M aq. NaOH (3x). The organic phase was dried (MgSO4)
and concentrated. Purification by flash chromatography (SiO2,
hexanes:EtOAc 4:1) gave 26f (181 mg, 0.44 mmol, 80%) as a
δ 7.89 (nfom, 2H), 7.76 (nfom, 2H), 6.23 (d, J = 10.4 Hz, 1H),
2.82–3.00 (m, 1H), 2.28–2.49 (m, 2H), 1.12 (t, J = 7.5 Hz, 3H),
1.09 (d, J = 6.7 Hz, 3H), and 0.89 (d, J = 6.8 Hz, 3H). 13C NMR
(75 MHz, CDCl3): δ 173.3, 169.9, 134.4, 131.5, 123.8, 79.3,
29.6, 27.3, 19.0, 17.9, and 8.9. IR (neat): 2981, 2970, 2939, 2880,
1776, 1755, 1719, 1472, 1391, 1373, 1356, 1333, 1199, 1168,
+
1083, 874, and 638 cm-1. HRMS: Calcd for C15H17NNaO4
[M+Na+] requires 298.1050; found 298.1056. MP: 122–125 ºC.
1-(1,3-Dioxoisoindolin-2-yl)-2-methylpropyl Isobutyrate (26b).
N,O-Acetal 26b was prepared according to General Procedure C
with isobutyryl chloride (56 µL, 0.53 mmol). Purification by
flash chromatography (SiO2, hexanes:EtOAc 4:1) gave 26b (148
mg, 0.51 mmol, 96%) as a white solid. 1H NMR (300 MHz,
CDCl3): δ 7.89 (nfom, 2H), 7.77 (nfom, 2H), 6.19 (d, J = 10.4
Hz, 1H), 2.83–3.02 (m, 1H), 2.61 (septet, J = 7.0 Hz, 1H), 1.19
(d, J = 7.0 Hz, 3H), 1.14 (d, J = 7.0 Hz, 3H), 1.10 (d, J = 6.7 Hz,
3H), and 0.90 (d, J = 6.8 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ
175.9, 166.9, 134.4, 131.5, 123.7, 79.3, 33.9, 29.6, 18.94, 18.89,
18.76, and 17.9. IR (neat): 2973, 2940, 2878, 1780, 1749, 1722,
1469, 1387, 1372, 1332, 1146, and 720 cm-1. HRMS: Calcd for
1
colorless solid. H NMR (300 MHz, CDCl3): δ 9.24 (t, J = 2.2
Hz, 1H), 9.18 (d, J = 2.2 Hz, 2H), 7.91 (nfom, 2H), 7.80 (nfom,
2H), 6.52 (d, J = 10.4 Hz, 1H), 3.09–3.27 (m, 1H), 1.20 (d, J =
6.6 Hz, 3H), and 1.00 (d, J = 6.8 Hz, 3H). 13C NMR (75 MHz,
CDCl3): δ 166.7, 161.6, 148.8, 134.8, 133.2, 131.3, 129.8, 124.1,
123,0, 81.5, 29.7, 19.2, and 17.9. IR (neat): 3098, 2970, 2880,
1738, 1743, 1724, 1545, 1371, 1345, 1265, 1157, 1080, and 718
+
cm-1. HRMS: Calcd for C19H15N3NaO8 [M+Na+] requires
436.0751; found 436.0758. MP: 154–156 ºC.
1-(1,3-Dioxoisoindolin-2-yl)-2-methylpropyl 4-Methoxybenzoate
(26g). N,O-Acetal 26g was prepared according to General
Procedure C with 4-methoxybenzoyl chloride (98 mg, 0.57
mmol). Purification by flash chromatography (SiO2,
hexanes:EtOAc 4:1) gave 26g (123 mg, 0.35 mmol, 61%) as a
+
C16H19NNaO4 [M+Na+] requires 312.1206; found 312.1203.
MP: 87–90 ºC.
1-(1,3-Dioxoisoindolin-2-yl)-2-methylpropyl
2-Phenylacetate
1
(26c). N,O-Acetal 26c was prepared according to General
Procedure C with phenylacetyl chloride (71 µL, 0.54 mmol).
Purification by flash chromatography (SiO2, hexanes:EtOAc 6:1)
gave 26c (127 mg, 0.38 mmol, 70%) as a clear oil. 1H NMR (300
MHz, CDCl3): δ 7.86 (nfom, 2H), 7.74 (nfom, 2H), 7.18–7.31
(m, 5H), 6.19 (d, J = 10.4 Hz, 1H), 3.68 (d, J = 15.1 Hz, 1H),
3.62 (d, J = 15.2 Hz, 1H), 2.81–2.99 (m, 1H), 1.00 (d, J = 6.6 Hz,
3H), and 0.87 (d, J = 6.9 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ
170.6, 166.9, 134.5, 133.4, 131.5, 129.5, 128.6, 127.3, 123.8,
79.8, 41.0, 29.6, 18.9, and 17.9. IR (neat): 2968, 1781, 1745,
1721, 1372, 1241, 1123, 1003, and 719 cm-1. HRMS: Calcd for
C20H19NNaO4+ [M+Na+] requires 360.1206; found 360.1207.
white solid. H NMR (300 MHz, CDCl3): δ 8.04 (d, J = 8.8 Hz,
2H), 7.87 (nfom, 2H), 7.73 (nfom, 2H), 6.91 (d, J = 8.8 Hz, 2H),
6.44 (d, J = 10.3 Hz, 1H), 3.85 (s, 3H), 2.97–3.16 (m, 1H), 1.15
(d, J = 6.6 Hz, 3H), and 0.96 (d, J = 6.8 Hz, 3H). 13C NMR (75
MHz, CDCl3): δ 167.1, 165.1, 163.8, 134.4, 132.2, 131.6, 123.8,
121.7, 113.8, 79.6, 55.6, 29.8, 19.1, and 18.0. IR (neat): 2968,
2940, 2880, 2840, 1780, 1731, 1606, 1512, 1372, 1257, 1168,
+
1088, and 720 cm-1. HRMS: Calcd for C20H19NNaO5 [M+Na+]
requires 376.1155; found 376.1163. MP: 101–103 ºC.
Bis(1-(1,3-dioxoisoindolin-2-yl)-2-methylpropyl) Adipate (26h).
Adipoyl chloride (39 µL, 0.27 mmol, 1 equiv) was added to a
mixture of isobutyraldehyde (110 µL, 1.2 mmol, 4.4 equiv),
potassium phthalimide (200 mg, 1.1 mmol, 4 equiv), NaI (160
mg, 1.1 mmol, 4 equiv), 4Å MS (100 mg), MeCN (1 mL), and
EtOAc (1 mL) at room temperature and with stirring. After 24 h,
the mixture was diluted in Et2O, and sequentially washed with
sat. aq. NH4Cl (1x) and 1 M aq. NaOH (3x). The organic phase
was dried (MgSO4) and concentrated. Purification by flash
chromatography (SiO2, hexanes:EtOAc 6:1) gave 26h (99 mg,
Benzyl (1-(1,3-Dioxoisoindolin-2-yl)-2-methylpropyl) Carbonate
(26d). N,O-Acetal 26d was prepared according to General
Procedure C with benzyl chloroformate (77 µL, 0.54 mmol).
Purification by flash chromatography (SiO2, hexanes:EtOAc 4:1)
1
gave 26d (73 mg, 0.21 mmol, 39%) as a colorless oil. H NMR
(300 MHz, CDCl3): δ 7.88 (nfom, 2H), 7.76 (nfom, 2H), 7.28–
7.37 (m, 5H), 6.12 (d, J = 10.5 Hz, 1H), 5.19 (d, J = 12.1 Hz,
1H), 5.08 (d, J = 12.1 Hz, 1H), 2.89–3.07 (m, 1H), 1.12 (d, J =
6.6 Hz, 3H), and 0.88 (d, J = 6.8 Hz, 3H). 13C NMR (75 MHz,
CDCl3): δ 166.8, 154.2, 134.8, 134.6, 131.5, 128.7, 128.6, 128.5,
123.9, 83.0, 70.1, 29.5, 19.0, and 17.9. IR (neat): 2969, 1784,
1
0.18 mmol, 67%) as a white solid. H NMR (300 MHz, CDCl3,
~1:1 mixture of two diastereomers): δ 7.83–7.91 (m, 4H), 7.72–
7.79 (m, 4H), 6.181 (d, J = 10.5 Hz, 2H, one diastereomer), 6.178
(d, J = 10.5 Hz, 2H, one diastereomer), 2.77–2.96 (m, 2H), 2.27–

ACCEPTED MANUSCRIPT
11
2.41 (m, 4H), 1.52–1.66 (m, 4H), 1.056 (d, J = 6.7 Hz, 3H),
1.051 (d, J = 6.6 Hz, 3H), 0.875 (d, J = 6.8 Hz, 3H), and 0.869
(d, J = 6.8 Hz, 3H). 13C NMR [75 MHz, CDCl3, ~1:1 mixture of
two diastereomers (diastereomeric carbons shown with *)]: δ
172.1, 167.0, 134.5, 131.5, 123.8, 79.3, 33.46*, 33.44*, 29.5,
24.00*, 23.98*, 19.0, and 17.9. IR (neat): 2967, 2940, 2880,
1780, 1748, 1721, 1469, 1380, 1372, 1125, 1015, and 720 cm-1.
yl)propyl) carbonate (32) described below]. 1H NMR (300
MHz, CDCl3): δ 8.16–8.22 (m, 2H), 8.11 (br d, J = 8.2 Hz, 2H),
7.60 (br t, J = 7.1 Hz, 1H), 7.41–7.53 (m, 5H), 7.20 (d, J = 8.7
Hz, 1H), 2.85–3.02 (m, 1H), 1.22 (d, J = 6.7 Hz, 3H), and 0.96
(d, J = 6.8 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 165.3, 164.7,
134.1, 130.6, 130.2, 129.0, 128.7, 128.6, 128.4, 127.1, 87.4, 32.6,
17.9, and 17.6. IR (neat): 3094, 3068, 2972, 2888, 2828, 1737,
1451, 1257, 1087, 1068, 1022, and 999 cm-1. HRMS (ESI-TOF):
+
HRMS: Calcd for C30H32N2NaO8 [M+Na+] requires 571.2051;
+
found 571.2050. MP: 156–159 ºC.
Calcd for C18H18N4NaO2 [M+Na+] requires 345.1322; found
345.1322.
1-(1H-Imidazol-1-yl)-2-methylpropyl Benzoate (27a). N,O-Acetal
27a was prepared according to General Procedure D with
imidazole (66 mg, 0.97 mmol) and benzoyl chloride (62 µL, 0.53
mmol). The product was found to not be stable under standard
flash chromatography conditions, however the crude product was
obtained in high purity and gave 27a (120 mg, 0.49 mmol, 93%)
1-(1H-Benzo[d][1,2,3]triazol-1-yl)-2-methylpropyl
Benzoate
(27e N1 regioisomer) and 1-(2H-Benzo[d][1,2,3]triazol-2-yl)-2-
methylpropyl Benzoate (27e N2 regioisomer). A mixture of
regioisomers of N,O-Acetal 27e was prepared according to
General Procedure D with benzotriazole (121 mg, 1.02 mmol)
and benzoyl chloride (62 µL, 0.53 mmol). Purification by flash
chromatography (SiO2, hexanes:EtOAc 6:1) gave a 3:2 mixture
of regioisomers of 27e (130 mg, 0.44 mmol, 83%). Analytical
data for each isolated regioisomer was acquired by partially
separating the mixture of regioisomers using flash
chromatography (SiO2, hexanes:EtOAc 6:1) as a colorless oil.
1
as a clear oil. H NMR (300 MHz, CDCl3): δ 8.03 (br d, J = 7.7
Hz, 2H), 7.78 (s, 1H), 7.59 (br t, J = 7.5 Hz, 1H), 7.45 (br t, J =
7.7 Hz, 2H), 7.15 (s, 1H), 7.09 (s, 1H), 6.40 (d, J = 9.4 Hz, 1H),
2.43–2.62 (m, 1H), 1.15 (d, J = 6.6 Hz, 3H), and 0.88 (d, J = 6.8
Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 165.1, 136.9, 133.7,
129.83, 129.78, 128.9, 128.6, 116.7, 83.8, 33.0, 18.5, and 17.7.
IR (neat): 3113, 3068, 3035, 2970, 2934, 2879, 1728, 1601,
1584, 1493, 1263, 1091, 1068, 1025, 989, 712, and 663 cm-1.
1
Analytical Data for 27e N1 regioisomer: H NMR (300 MHz,
CDCl3): δ 8.04–8.10 (m, 3H), 7.87 (d, J = 8.4 Hz, 1H), 7.51–7.62
(m, 2H), 7.44 (br t, J = 7.7 Hz, 2H), 7.38 (d, J = 7.6 Hz, 1H),
7.13 (d, J = 9.7 Hz, 1H), 3.14–3.28 (m, 1H), 1.28 (d, J = 6.7 Hz,
3H), and 0.86 (d, J = 6.7 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ
165.4, 145.9, 134.0, 133.0, 130.1, 128.7, 128.2, 124.5, 120.2,
110.4, 84.7, 32.2, 18.8, and 18.1. IR (neat): 3065, 2971, 2928,
2876, 1731, 1452, 1257, 1091, 1025, 748, and 711 cm-1. HRMS
+
HRMS (ESI-TOF): Calcd for C14H17N2O2 [M+H+] requires
245.1285; found 245.1288.
2-Methyl-1-(1H-pyrazol-1-yl)propyl Benzoate (27b). N,O-Acetal
27b was prepared according to General Procedure D with
pyrazole (69 mg, 1.0 mmol) and benzoyl chloride (62 µL, 0.53
mmol). Purification by flash chromatography (SiO2,
hexanes:EtOAc 6:1) gave 27b (118 mg, 0.36 mmol, 68%) as a
(ESI-TOF): Calcd for C17H18N3O2 [M+H+] requires 296.1394;
+
found 296.1417. Analytical Data for 22e N2 regioisomer: 1H
NMR (300 MHz, CDCl3): δ 8.12 (br d, J = 7.8 Hz, 2H), 7.90
(nfom, 2H), 7.58 (br t, J = 7.7 Hz, 1H), 7.44 (br t, J = 7.7 Hz,
2H), 7.39 (nfom, 2H), 7.17 (d, J = 9.0 Hz, 1H), 2.93–3.11 (m,
1H), 1.24 (d, J = 6.7 Hz, 3H), and 0.86 (d, J = 6.8 Hz, 3H). 13C
NMR (75 MHz, CDCl3): δ 165.0, 144.3, 133.9, 128.8, 128.6,
127.14, 127.09, 118.8, 90.5, 33.1, 18.2, and 17.7. IR (neat): 3068,
2972, 2937, 2878, 1737, 1601, 1564, 1452, 1247, 1089, 748, and
1
colorless oil. H NMR (300 MHz, CDCl3): δ 8.07 (br d, J = 8.2
Hz, 2H), 7.70 (br d, J = 2.3 Hz, 1H), 7.60 (br s, 1H), 7.56 (br t, J
= 7.8 Hz, 1H), 7.42 (br t, J = 8.2 Hz, 2H), 6.49 (d, J = 9.5 Hz,
1H), 6.24–6.28 (m, 1H), 2.81–2.99 (m, 1H), 1.15 (d, J = 7.3 Hz,
3H), and 0.83 (d, J = 6.7 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ
165.6, 140.8, 133.6, 130.6, 130.0, 129.2, 128.5, 105.7, 87.2, 32.1,
18.5, and 17.8. IR (neat): 3107, 3064, 3035, 2971, 2935, 2878,
1725, 1452, 1399, 1299, 1091, 987, and 711 cm-1. HRMS (ESI-
709 cm-1. HRMS (ESI-TOF): Calcd for C17H18N3O2 [M+H+]
requires 296.1394; found 296.1394.
+
+
TOF): Calcd for C14H17N2O2 [M+H+] requires 245.1285; found
245.1297.
2-((4-Chlorophenyl)(phenyl)methyl)isoindoline-1,3-dione (28).
TiCl4 (100 µL, 0.91 mmol) was added to a mixture of N,O-acetal
8s (100 mg, 0.30 mmol) in benzene (0.6 mL) CH2Cl2 (0.4 mL) at
room temperature with stirring. After 24 h, the reaction mixture
was diluted in EtOAc, washed with sat. aq. NH4Cl, dried
(MgSO4), and concentrated. Purification by gradient flash
chromatography (SiO2, hexanes:EtOAc 9:1 to 6:1) gave 28 (84
mg, 0.24 mmol, 80%) as a white solid. 1H NMR (300 MHz,
CDCl3): δ 7.85 (nfom, 2H), 7.73 (nfom, 2H), 7.28–7.4 (m, 9H),
and 6.68 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 167.9, 137.8,
136.8, 134.3, 133.7, 131.8, 130.3, 128.65, 128.62 (2xC), 128.0,
123.6, and 57.2. IR (neat): 3060, 3030, 2900, 1770, 1714, 1492,
1382, 1355, 1328, 1090, and 720 cm-1. HRMS (ESI-TOF): Calcd
2-Methyl-1-(1H-1,2,4-triazol-1-yl)propyl Benzoate (27c). N,O-
Acetal 22c was prepared according to General Procedure D with
1,2,4-triazole (71 mg, 1.0 mmol) and benzoyl chloride (62 µL,
0.53 mmol). The product was found to not be stable under
standard flash chromatography conditions, however the crude
product was obtained in high purity and gave 27c (115 mg, 0.47
1
mmol, 89%) as a colorless oil. H NMR (300 MHz, CDCl3): δ
8.42 (s, 1H), 8.07 (br d, J = 8.1 Hz, 2H), 8.01 (s, 1H), 7.59 (br t, J
= 7.7 Hz, 1H), 7.45 (br t, J = 7.6 Hz, 2H), 6.57 (d, J = 9.2 Hz,
1H), 2.82–2.99 (m, 1H), 1.18 (d, J = 6.7 Hz, 3H), and 0.87 (d, J =
6.7 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 165.2, 152.4, 133.7,
129.9 (3xC), 128.54, 128.50, 84.7, 31.4, 18.1, and 17.7. IR
(neat): 3123, 3066, 2972, 2936, 2879, 1728, 1508, 1261, 1091,
and 711 cm-1. HRMS (ESI-TOF): Calcd for C13H16N3O2+ [M+H+]
requires 246.1237; found 246.1252.
+
for C21H1435ClNNaO2 [M+H+] requires 370.0605; found
370.0590. MP: 156–157 ºC.
(4-Chlorophenyl)(phenyl)methanamine (29). Phthalimide 28 (59
mg, 0.17 mmol), ethanol (680 µL), and dichloromethane (230
µL) were added to a culture tube, capped with a Teflon®-lined
screw cap, and heated to 40 ºC. After the mixture became
homogenous, hydrazine hydrate (33 µL, 0.68 mmol) was added,
the Teflon®-lined screw cap was replaced, and the mixture was
heated at 80 ºC with stirring. After 24 h, the mixture was cooled
to rt, filtered through celite [ethanol:dichloromethane (3:1)
eluent], and acidified with 3M aq. HCl. The organic phase was
2-Methyl-1-(5-phenyl-2H-tetrazol-2-yl)propyl Benzoate (27d).
N,O-Acetal 27d was prepared according to General Procedure D
with 5-phenyl-1H-tetrazole (121 mg, 0.83 mmol) and benzoyl
chloride (62 µL, 0.53 mmol). Purification by flash
chromatography (SiO2, hexanes:EtOAc 6:1) gave 27d (105 mg,
0.33 mmol, 62%) as a colorless oil. The product structure is
inferred from a related reaction where ethyl chloroformate was
used in place of benzoyl chloride to give known8i N,O-acetal 32
[cf. synthesis of ethyl (2-methyl-1-(5-phenyl-2H-tetrazol-2-

ACCEPTED MANUSCRIPT
12
Tetrahedron
removed and the organic impurities were removed by washing
the NSF Major Research Instrumentation (NSF-MRI) Grant
Program (CHE-1429616). Calculations were performed using the
Midwest Undergraduate Computational Chemistry Consortium
(MU3C) facility at Hope College (funding via NSF-MRI: CHE-
1039925).
the aqueous phase with EtOAc (3x). The resulting aqueous
mixture was basified to pH>10 with 1M aq. NaOH and extracted
with dichloromethane (3x). The dichloromethane extracts were
combined, dried (MgSO4), and concentrated to give 29 (19 mg,
0.087 mmol, 51%). 1H NMR (300 MHz, CDCl3): δ 7.16–7.48 (m,
1
9H), 5.18 (s, 1H), and 1.93 (br s, 2H). The H NMR data is in
References and notes
good agreement with previously reported characterization
results.24
2-(2,3-Dihydro-1H-inden-1-yl)isoindoline-1,3-dione (30). TiCl4
(100 µL, 0.91 mmol) was added to a mixture of N,O-acetal 8n
(105 mg, 0.33 mmol) in CH2Cl2 (3.1 mL) at room temperature
with stirring. After 24 h, the reaction mixture was diluted in
EtOAc, washed with sat. aq. NH4Cl, dried (MgSO4), and
concentrated. Purification by flash chromatography (SiO2,
hexanes:EtOAc 6:1) gave 30 (57 mg, 0.21 mmol, 64%). 1H NMR
(300 MHz, CDCl3): δ 7.82 (nfom, 2H), 7.71 (nfom, 2H), 7.07–
7.33 (m, 4H), 5.88 (dd, J = 6.7, 8.9 Hz, 1H), 3.37 (ddd, J = 5.1,
8.9, 16.1 Hz, 1H), 3.00 (ddd, J = 7.7, 7.7, 15.7 Hz, 1H), and
2.41–2.62 (m, 2H). The 1H NMR data is in good agreement with
previously reported characterization results.25
1
.
.
Mosey, R. A.; Floreancig, P. E. Nat. Prod. Rep. 2012, 29, 980.
(a) Cichewicz, R. H.; Valeriote, F. A.; Crews, P. Org. Lett.
2
2004, 6, 1951. (b) Pettit, G. R.; Xu, J.-P.; Chapuis, J.-C.; Pettit,
R. K.; Tackett, L. P.; Doubek, D. L.; Hooper, J. N. A.; Schmidt,
J. M. J. Med. Chem. 2004, 47, 1149.
3. Isolation: (a) Pavan, M.; Bo, G. Physiol. Comp. Oecol. 1953,
3, 307. Structure Elucidation: (b) Cardani, C.; Ghiringhelli, D.;
Mondelli, R.; Quilico, A. Tetrahedron Lett. 1965, 6, 2537. (c)
Furusaki, A.; Watanabe, T.; Matsumoto, T.; Yanagiya, M.
Tetrahedron Lett. 1968, 9, 6301. Review of Bioactivity Studies:
(c) Narquizian, R.; Kocienski, P. J. In The Role of Natural
Products in Drug Discovery; Mulzer, J., Bohlmann, R., Ed.;
Springer: New York, 2000; pp 25–56.
2,3-Dihydro-1H-inden-1-amine (31). Phthalimide 30 (110 mg,
0.42 mmol), ethanol (1.7 mL), and dichloromethane (0.57 mL)
were added to a culture tube, capped with a Teflon®-lined screw
cap, and heated to 40 ºC. After the mixture became homogenous,
hydrazine hydrate (82 µL, 1.7 mmol) was added, the Teflon®-
lined screw cap was replaced, and the mixture was heated at 80
ºC with stirring. After 24 h, the mixture was cooled to rt, filtered
through celite [ethanol:dichloromethane (3:1) eluent], and
acidified with 3M aq. HCl. The organic phase was removed and
the organic impurities were removed by washing the aqueous
phase with EtOAc (3x). The resulting aqueous mixture was
basified to pH>10 with 1M aq. NaOH and extracted with
dichloromethane (3x). The dichloromethane extracts were
combined, dried (MgSO4), and concentrated to give 31 (37 mg,
4. Wan, S.; Wu, F.; Rech, J. C.; Green, M. E.; Balachandran, R.;
Horne, W. S.; Day, B. W.; Floreancig, P. E. J. Am. Chem. Soc.
2011, 133, 16668.
5. For representative examples: (a) Ferraris, D.; Dudding, T.;
Young, B.; Drury, W. J.; Lectka, T. J. Org. Chem. 1999, 64,
2168. (b) Yamazaki, N.; Ito, T.; Kibayashi, C. Org. Lett. 2000, 2,
465. (c) Sugiura, M.; Hagio, H.; Hirabayashi, R.; Kobayashi, S.
J. Am. Chem. Soc. 2001, 123, 12510. (d) Gizecki, P.; Dhal, R.;
Poulard, C.; Gosselin, P.; Dujardin, G. J. Org. Chem. 2003, 68,
4338.
6. (a) Graham, T. J. A.; Shields, J. D.; Doyle, A. G. Chem. Sci.
2011, 2, 980. (b) Sylvester, K. T.; Wu, K.; Doyle, A. G. J. Am.
Chem. Soc. 2012, 134, 16967.
1
0.28 mmol, 67%). H NMR (300 MHz, CDCl3): δ 7.09–7.42 (m,
7. (a) Johnson, T.; Lautens, M. Org. Lett. 2013, 15, 4043. (b)
4H), 4.37 (dd, J = 7.4, 7.5 Hz, 1H), 2.97 (ddd, J = 3.5, 8.7, 15.9
Hz, 1H), 2.81 (ddd, J = 8.2, 8.2, 16.4 Hz, 1H), 2.51 (dddd, J =
3.5, 7.5, 7.5, 12.4 Hz, 1H), 2.1 (br s, NH2), and 1.69 (dddd, J =
Johnson, T.; Luo, B.; Lautens, M. J. Org. Chem. 2016, 81, 4923.
8. Representative reports on preparing N,O-acetals: (a) Katritzky,
A. R.; Pernak, J.; Fan, W. Q.; Saczewski, F. J. Org. Chem. 1991,
56, 4439. (b) Katritzky, A. R.; Fan, W. Q.; Black, M.; Pernak, J.
J. Org. Chem. 1992, 57, 547. (c) Renaud, P.; Stojanovic, A.
Tetrahedron Lett. 1996, 37, 2569. (d) Wan, S.; Green, M. E.;
Park, J.-H.; Floreancig, P. E. Org. Lett. 2007, 9, 5385. (e)
Vellalath, S.; Čorić, I.; List, B. Angew. Chem., Int. Ed. 2010, 49,
9749. (f) Li, M.; Luo, B.; Liu, Q.; Hu, Y.; Ganesan, A.; Huang,
P.; Wen, S. Org. Lett. 2014, 16, 10. (g) Xu, K.; Wang, Z.; Zhang,
J.; Yu, L.; Tan, J. Org. Lett. 2015, 17, 4476. (h) Sun, J.; Zhang,
Y.; Mathan, S.; Wang, Y.; Pan, Y. J. Org. Chem. 2016, 81, 3380
and references cited therein. (i) Piotrowski, D. W.; Kamlet, A. S.;
Dechert-Schmitt, A.-M. R.; Yan, J.; Brandt, T. A.; Xiao, J.; Wei,
L.; Barrila, M. T. J. Am. Chem. Soc. 2016, 138, 4818.
1
8.3, 8.3, 8.3, 12.5, 1H). The H NMR data is in good agreement
with previously reported characterization results.26
Ethyl (2-Methyl-1-(5-phenyl-2H-tetrazol-2-yl)propyl) Carbonate
(32). To aid with structure assignment confirmation of 27d, N,O-
Acetal 32 was prepared according to General Procedure D with
5-phenyl-1H-tetrazole (121 mg, 0.83 mmol) and ethyl
chloroformate (50 µL, 0.53 mmol) (cf. equation shown below).
1H NMR (300 MHz, CDCl3): δ 8.16–8.24 (m, 2H), 7.43–7.54 (m,
3H), 6.78 (d, J = 8.8 Hz, 1H), 4.15–4.32 (m, 2H), 2.80 (nfom,
1H), 1.31 (t, J = 7.15 Hz, 3H), 1.19 (d, J = 6.7 Hz, 3H), and 0.87
(d, J = 6.8 Hz, 3H). The crude product (125 mg, 0.43 mmol,
1
81%) was sufficiently pure for routine H NMR analysis, which
was in good agreement with reported data.8i
9. Katritzky, A. R.; Pastor, A.; Voronkov, M. V. J. Heterocycl.
Chem. 1999, 36, 777.
10. The low yield is reflective of the sluggish nature of the
reactions (cf. conversion was less than 70%) as opposed to
consumption of starting material by competing pathways.
11. For this reason, use of aldehyde substrates that contain trace
carboxylic acid impurities will lead to diminished yields. This is
overcome by using freshly distilled aldehydes or adding 0.1–1
equiv Et3N.
Acknowledgments
This research was supported by the American Chemical
Society Petroleum Research Fund Undergraduate New
Investigator Grant Program. Hi-Res mass spectrometry data was
acquired from instrumentation purchased with funds provided by
12. Sodium and lithium phthalimide were prepared by modifying
a procedure in the following report to use either NaOH or

ACCEPTED MANUSCRIPT
13
LiOH•H2O, respectively: Salzberg, P. L.; Supniewski, J. V. Org.
Synth. 1927, 7, 8.
13. The conversions obtained with sodium phthalimide (i.e.,
99%), potassium phthalimide (i.e., 49%), and lithium phthalimide
(i.e., 24%) created a trend similar to that observed when
comparing the %yields. An expanded version of Table 1 with the
conversion for each entry is included in the Supplementary Data.
14. Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 120, 215.
15. Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem.
B. 2009, 113, 6378.
16. No product was observed when phenol-containing aldehydes
were used.
17. Nicolaou, K. C.; Adsool, V. A.; Hale, C. R. H. Org. Lett.
2010, 12, 1552.
18. A sample of N-acetyl phthalimide (7) that was left open and
exposed to ambient air, humidity, and light for 30 days
participated in the reported reaction to prepare 8a without any
noticeable decrease in reaction efficiency.
19. Opalka, C. J.; D’Ambra, T. E.; Faccone, J. J.; Bodson, G.;
Cossement, E. A Synthesis 1995, 1995, 766.
20. Ma, G.; Xu, Z.; Zhang, P.; Liu, J.; Hao, X.; Ouyang, J.;
Liang, P.; You, S.; Jia, X. Org. Process Res. Dev. 2014, 18,
1169.
21. Goodman, C. A.; Hamaker, C. G.; Hitchcock, S. R.
Tetrahedron Lett. 2013, 54, 6012.
22
4036.
23 Li, G.; Arisawa, M.; Yamaguchi, M. Asian Journal of
. Du, X.-W.; Ghosh, A.; Stanley, L. M. Org. Lett. 2014, 16,
.
Organic Chemistry 2013, 2, 983.
24. Wang, D.; Cao, P.; Wang, B.; Jia, T.; Lou, Y.; Wang, M.;
Liao, J. Org. Lett. 2015, 17, 2420.
25. Sun, J.; Wang, Y.; Pan, Y. J. Org. Chem. 2015, 80, 8945.
26. Guijarro, D.; Pablo, O.; Yus, M. J. Org. Chem. 2010, 75,
5265.