The development of carbon-carbon bond forming reactions of aminal radicals

Article abstract of DOI:10.1016/j.tet.2014.12.067

Aminal radicals were generated and used in synthetic reactions for the first time. Aminal radicals are formed from aminals by radical translocation using AIBN and a stoichiometric hydrogen atom donor, or by SmI₂ reduction of N-acyl amidines or amidinium ions in the presence of a proton source. Aminal radicals were found to participate in inter- and intramolecular C-C bond forming reactions with electron deficient alkenes. Chemical yields were as high as 99%.

Full text of DOI:10.1016/j.tet.2014.12.067

Tetrahedron 71 (2015) 1448e1465
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
The development of carbonecarbon bond forming reactions of
aminal radicals
*
David A. Schiedler, Jessica K. Vellucci, Yi Lu, Christopher M. Beaudry
Department of Chemistry, Oregon State University, 153 Gilbert Hall, Corvallis, OR 97331-4003, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 October 2014
Received in revised form 18 December 2014
Accepted 18 December 2014
Available online 10 January 2015
Aminal radicals were generated and used in synthetic reactions for the first time. Aminal radicals are
formed from aminals by radical translocation using AIBN and a stoichiometric hydrogen atom donor, or
by SmI2 reduction of N-acyl amidines or amidinium ions in the presence of a proton source. Aminal
radicals were found to participate in inter- and intramolecular CeC bond forming reactions with electron
deficient alkenes. Chemical yields were as high as 99%.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Aminal radicals
Alkaloids
Samarium iodide
Radical translocation
1. Introduction
electron lone pair on the adjacent nitrogen atom and react with
alkenes to give products of CeC bond formation.9 This reactivity has
Many biologically active molecules, including pharmaceuticals,
contain one or more nitrogen atoms. As a result, nitrogen-rich
compounds, such as alkaloids and pharmaceuticals, make com-
pelling synthetic targets.1 However, the complex reactivity of ni-
trogen can be problematic in synthesis. The ability to quaternize,
the Lewis basic lone pair, and the weakly acidic NeH protons found
in nitrogen-containing molecules often give rise to undesired
reactivity.
proven useful for the synthesis of heterocycles as well as in the total
synthesis of alkaloids.10 Carbon-centered radicals bearing two ad-
jacent heteroatoms, such as acetal radical 2, are also known to
undergo CeC bond forming reactions with alkenes (Scheme 1, Eq.
2). Additionally, N,S- and N,O-acetal radicals (3) have been pre-
sumed as intermediates in CeC bond forming reactions (Scheme 1,
Eq. 3).11
Carbon-centered radicals bearing two adjacent nitrogen atoms
(i.e., aminal radicals) have been implicated as intermediates in the
free radical and radiative damage of DNA nucleotide bases,12 they
have been experimentally generated and studied spectroscopi-
cally,13 and long-lived aminal radicals have been isolated.14 Appli-
cations of aminal radicals include their use as photochromic dyes15
and as tools for mechanistic investigations.16 Although there are
reports of fragmentation,17 protonation,18 and dimerization re-
actions of aminal radicals, there had been no reports of their syn-
thetic utility prior to recent work from our laboratory.19
In order to mask the complex Lewis acidebase reactivity of ni-
trogen, synthetic chemists often resort to the use of protective
groups.2 Other strategies, which have proven successful for the
synthesis of nitrogen-containing structures include opting to install
nitrogen late in the synthesis3 or in the form of a less reactive
functional group (e.g., as a nitro4 or nitrile5 group). An alternative
means to circumvent the pitfalls of alkaloid synthesis is the use of
single electron reactivity (i.e., free radical reactions). Free radicals
are known to tolerate heteroatom lone pairs, and NeH bonds are
resistive to homolytic cleavage.6 As a result, free radical reactions
have been used successfully for key CeC bond forming reactions in
the synthesis of complex alkaloids (e.g., Scheme 1, Eq. 1).7
The addition of carbon-centered radicals bearing heteroatoms
Having considered the known reactivity of acetal and a-ami-
noalkyl radicals, the creation of a new reaction was envisioned
wherein an aminal radical would undergo addition to an alkene to
give the product of CeC bond formation. Computational studies
indicated that aminal radicals are 1e2 kcal/mol more stable than
to CeC multiple bonds has been known for over 50 years.8
a-
Aminoalkyl radicals, such as 1 (Scheme 1), gain stability from the
analogous a
-aminoalkyl radicals.20 This suggested that it would be
possible to selectively generate aminal radicals in the presence of
carbon atoms bearing a single nitrogen atom. Based on these con-
siderations, we postulated that aminal radical intermediates would
be well suited for the construction of the carbon framework in
* Corresponding author. Tel.: þ1 541 737 6746; fax: þ1 541 737 2062; e-mail
address: christopher.beaudry@oregonstate.edu (C.M. Beaudry).
http://dx.doi.org/10.1016/j.tet.2014.12.067
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

D.A. Schiedler et al. / Tetrahedron 71 (2015) 1448e1465
1449
Scheme 1. Selected transformations involving radical intermediates bearing a-heteroatoms.
nitrogen-rich molecules. For example, Fig. 1 shows a selection of
biologically active aminal containing natural products, which have
attracted the interest of many synthetic chemists.21 Furthermore,
commercial pharmaceuticals quinethazone and metolazone also
possess the aminal functional group.
aminals, which do not bear an electron-withdrawing group,
a deuterium labeling study on the translocation reactions of ami-
nals, which do not bear an electron-withdrawing group, and ap-
plications of the translocation method to acyclic aminals relevant to
the synthesis of indole alkaloids.
2. Results and discussion
In 1958, Juveland reported the generation of
a-aminoalkyl
radical intermediate 4 under peroxide initiated conditions (Scheme
2, Eq. 1).22 Treatment of piperidine with di-tert-butylperoxide in
the presence of 1-octene yielded 2-octyl piperidine. Extension of
this method to the generation of aminal radicals could involve the
treatment of an aminal with di-tert-butylperoxide in the presence
of
a suitable radical acceptor (Scheme 2, Eq. 2). Tetrahy-
droisoquinazoline (5) was chosen because it was easy to prepare, it
is chromatographically stable, and it contains a chromophore,
which allowed for facile monitoring of reaction progress.
Following Juveland’s procedure, 5 was heated in the presence of
di-tert-butylperoxide and 1-octene in a sealed tube. The reaction
produced an intractable mixture of products and none of the de-
sired product 6 was observed. In an effort to affect cleaner re-
activity, modified reaction conditions were investigated. Lowering
the reaction temperature resulted in no reaction. Performing the
reaction neat, tethering the radical acceptor to the substrate, or
using activated alkenes as radical acceptors all resulted in the for-
mation of a complex mixture of products.23
Based on these results, two plausible explanations were for-
mulated. Either the desired aminal radical 7 was generated, and it
was reacting in an unselective manner to give the observed de-
composition, or aminal radical 7 had not been generated and the
Fig. 1. Selected aminal containing alkaloids and pharmaceuticals.
Herein we give a full account of the development of aminal
radical reactivity for use in synthesis. In addition to expanded
discussions of the results previously reported, we describe our
initial efforts to generate aminal radicals under peroxide initiated
conditions, the efforts to optimize translocation reactions of

1450
D.A. Schiedler et al. / Tetrahedron 71 (2015) 1448e1465
Scheme 2. Extension of Juveland’s method.
observed degradation was arising from other reaction pathways.
Unable to easily distinguish between these possibilities, an alter-
native method for the generation of aminal radicals was sought.
Ideally, this method would incorporate a functional handle that
could be used to determine whether aminal radicals were being
generated.
competent. However, in addition to the desired product 13, iso-
meric product 14,27 over addition product 15, and dehalogenated
product 16 were observed (Table 1). Formation of the undesired
product 14 is competitive with the formation of desired product 13
as a result of the stability of the
a-aminobenzylic radical from
which it presumably arises. The formation of dehalogenated 16 was
not surprising given that similar reaction conditions have been
used to perform radical dehalogenation.28 Although Curran re-
ported the oxidation of 2-iodobenzyl ethers under similar reaction
conditions,29 no amidine formation was observed.
Radical translocation24 of 2-iodobenzyl (IBn) protected amine 8
with AIBN and Bu3SnH in the presence of methyl acrylate gives
alkylated product 9 (Scheme 3).25 Reactions of this type proceed
through the generation of a phenyl radical (10) followed by 1,5-H
atom transfer to form an
a
-aminoalkyl radical intermediate 11.
Having successfully demonstrated that aminal radical in-
termediates could be generated and added to alkenes using the
radical translocation method, efforts were turned to reaction op-
The -aminoalkyl radical then adds to the olefin and gives 9 after H
a
atom abstraction from Bu3SnH.
Scheme 3. Protective radical translocation.
The application of radical translocation as a means to generate
aminal radicals was particularly attractive because it would provide
a functional handle through which problematic reactivity might be
diagnosed. Specifically, the loss of iodide is diagnostic for the for-
mation of a phenyl radical. Deuteration experiments could be used
to determine whether the desired 1,5-H atom abstraction had oc-
curred if the reaction failed to produce the aminal radical addition
product. Additionally, the necessary 2-iodobenzyl substituted
starting material 12 (Table 1) could be easily prepared by alkylation
of 5, and the product of the translocation reaction (13) would be
a benzyl protected aminal.
N-2-Iodobenzyl-tetrahydroquinazoline (12) was prepared from
5 and 2-iodobenzyliodide. Treatment of the protected aminal with
AIBN and Bu3SnH in the presence of methyl acrylate yielded some
of the desired aminal radical product 13 (Table 1, entry 1).26 This
indicated that the desired aminal radical is synthetically
timization. Variation of the Bu3SnH equivalents had little effect on
the product distribution; however, the yield of 13 decreased when
less than 2 equiv were added (Table 1, entries 1e3). Adjustment of
the acrylate equivalents showed that only trace amounts of the
desired products were formed when less than 2 equiv were used
(entry 4). Increasing the stoichiometry of the acrylate up to 5 equiv
showed little effect on the product distribution or isolated yield
(entries 5, 6). However, using a large excess of the acceptor resulted
in a decrease in yield (entry 7). Decreasing the time of addition from
10 h to 1 h was found to partially suppress the formation of the over
addition product 15 (entries 8, 9). Systematic variation of the re-
action concentration showed that the optimal yield was obtained
with a concentration of 0.1 M with respect to the aminal, but the
reaction remained unselective (entries 10e12). A solvent screen
showed that toluene and cyclohexane were also amenable to the
desired reactivity while use of carbon tetrachloride resulted in

D.A. Schiedler et al. / Tetrahedron 71 (2015) 1448e1465
1451
Table 1
Attempted optimization of radical translocation
Entry
Bu3SnH (equiv)
Acrylate (equiv)
Addition time (h)
Concentration (M)
Solvent
13þ14a (%)
16a (%)
17a (%)
1
2
3
4
5
6
7
8
3.9
2.0
0.9
2.0
2.0
2.0
2.0
3.9
3.9
3.9
2.0
2.0
2.0
2.0
2.0
3
3
3
1
3
5
10
3
3
3
10
1
1
1
1
1
1
10
1
10
1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.01
0.1
0.5
0.1
0.1
0.1
PhH
PhH
PhH
PhH
PhH
PhH
PhH
PhH
PhH
PhH
PhH
PhH
CyH
PhMe
CCI4
32
28
12
4
28
16
6
32
12
16
28
14
6
12
18
9
8
0
9
8
4
18
0
19
9
24
37
14
34
37
17
18
24
23
9
9
10
11
12
13
14
15
3
3
3
3
37
25
12
18
1
1
1
1
5
3
6
3
Decomposition
a
Isolated yields.
decomposition (entries 13e15). Benzene was chosen as the optimal
solvent as it was easily removed by rotary evaporation, provided
superior yields, and possessed favorable solubility properties. In
total, more than one hundred conditions were screened but all
failed to cleanly produce 13 in high chemical yield.
at the ortho-position of the benzyl group while only 21% was in-
corporated on the tetrahydroquinazoline ring. Assuming that the
1,5-H atom transfer is irreversible, this result suggested that the
aminal radical, once formed, reacted smoothly with the acrylate
acceptor and proceeded to the desired product. However, the rate
of D atom abstraction from Bu3SnD was competitive with that of
1,5-H atom abstraction from the aminal.
Based on this result, it was reasoned that the use of a terminal
reductant, which undergoes H atom abstraction at a slower rate
than Bu3SnH would likely decrease the amount of undesired
dehalogenation observed. (TMS)3SiH, a common substitute for tin
hydrides in radical processes,31 is known to undergo H atom ab-
straction at a rate approximately one fifth than that of Bu3SnH.32
Unfortunately, substitution of (TMS)3SiH for Bu3SnH in the re-
action mixture resulted in no reaction. It was reasoned that the rate
of H atom abstraction from (TMS)3SiH may have been insufficient to
sustain the radical chain. Ph3GeH is known to undergo H atom
abstraction at a rate slower than that of Bu3SnH and faster than that
Of the undesired side products formed in the reaction of 12, the
dehalogenation product 16 was always the most abundant. Pre-
sumably, 16 results from the reaction of a radical intermediate with
Bu3SnH before it has had sufficient opportunity to react with the
acrylate. A deuteration experiment was performed in order to
probe whether this undesired reduction was occurring before or
after the 1,5-H atom transfer event. After homolysis of the CeI
bond, a phenyl radical is generated. If the 1,5-H atom transfer is
slow and the phenyl radical reacts with Bu3SnD,30 then a deuterium
atom should be incorporated at the ortho-position of the benzyl
group (Scheme 4, pathway A). However, if the 1,5-H atom transfer
event occurs rapidly, then the deuterium would be incorporated on
the aminal containing ring (pathway B).
Scheme 4. Deuterium Incorporation in the dehalogenated side product.
A solution of aminal 12 and methyl acrylate was heated to reflux
while a solution of Bu3SnD and AIBN in benzene was added over
a period of 1 h. Deuterium NMR analysis of the dehalogenated
product (17) revealed that 79% of the deuterium was incorporated
of (TMS)3SiH.33 However, use of Ph3GeH as a terminal reductant
also failed to give any product formation.
Reasoning that substitution of the benzylic position would elimi-
nate undesired products resulting from reaction of the
a-

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D.A. Schiedler et al. / Tetrahedron 71 (2015) 1448e1465
aminobenzylic radical, dihydroquinizolinone 18 was investigated.
Treatment of 18 with the standard reaction conditions resulted in
significantly cleaner reactivity than that of aminal 12. The desired
product 19 was obtained in a synthetically useful yield along with
a small amount of the imide 20, which presumably resulted from
subsequent intramolecular cyclization of the desired product (Table 2,
It was unclear whether the improved results obtained with
these dihydroquinizolinone-derived substrates were simply an ef-
fect of blocking the benzylic position, or if there was a stabilizing
effect given by the carbonyl. In order to probe this, a side by side
comparison of substrates 32 and 33 was performed (Scheme 5). It
was found that 32, which lacks an electron-withdrawing group,
Table 2
Optimization of the translocation method with N-acyl aminals
Entry
R3XH
BnSH (equiv)
AIBN (equiv)
Acrylate (equiv)
19 (%)
20 (%)
1
2
3
4
5
6
7
8
Bu3SnH
Bu3SnH
(TMS)3SiH
Ph2SiH2
None
Bu3SnH
(TMS)3SiH
Bu3SnH
0
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0
3
3
3
3
3
5
5
5
49
75
72
12
0
17
0.9
0.9
0.9
0.9
0.1
0.1
0.9
No reaction
No reaction
26
70
18
60
21
0
Table 3
Examination of radical acceptor scope for the translocation method
entry 1). Surprisingly, the reactions of dihydroquinizolinone 18 were
found to be substantially more robust than those of tetrahy-
droquinazoline 12. While reactions using aminal 12 had required
rigorously dried and degassed solvent, aminal 18 reacted smoothly
even when wet, non-degassed solvent was used. Encouraged by these
results, optimization studies were carried out.
Thiols have been shown to aid in H atom transfer events.34 It
was found that the addition of substoichiometric quantities of
benzyl mercaptan provided increased reaction yields (Table 2, entry
2). (TMS)3SiH, which is non-toxic,35 was found to be an effective H
atom donor when BnSH was used (entry 3). No reaction was ob-
served when Ph2SiH2 was used (entry 4). When hydrides were
omitted and BnSH was used, no reaction was observed (entry 5).
The loading of the thiol had no appreciable effect on the reaction
yield; however, the formation of 20 decreased in the case when
BnSH was used with higher loadings (entries 2 and 3 vs 6 and 7). In
the absence of AIBN, only modest product formation was observed
(entry 8); it is possible that some CeI bond homolysis occurred
thermally.
Entry
Product
R3XH
Yield (%)
1
2
Bu3SnH
65
22
(TMS)3SiH
3
4
Bu3SnH
79
56
(TMS)3SiH
Having found reaction conditions suitable for the formation of
aminal radicals and their addition to alkenes, the substrate scope
with respect to the radical acceptor was investigated. It was found
that a variety of electron poor alkenes, including acrylates (21),
acrylonitrile (22), and acrolein (23) act as suitable radical acceptors
(Table 3, entries 1e6). In contrast, unactivated (24) and electron-
rich alkenes (25) did not participate in the reaction (entries 7 and
5
6
Bu3SnH
57, 1:1 dr
20, 1:1 dr
(TMS)3SiH
8). These data suggested that, like their a-aminoalkyl radical ana-
logues, N-acyl aminal radicals are nucleophilic in character and
react selectively with electrophilic radical acceptors.
7
8
Bu3SnH
Bu3SnH
0
0
A variety of aminal substrates were investigated. The reaction
tolerated substitution at either aminal nitrogen, and isomeric
aminal 26 participated in the reaction to give products 27e29
(Table 4, entries 1e6). The reaction of phenyl substituted aminal 30,
which would give rise to a tertiary benzylic aminal radical, failed to
produce any of the desired product 31 (entry 7). It is possible that
steric interactions between the phenyl substituent and the radical
translocation group disfavored a conformation that would allow
the 1,5-H atom abstraction to occur.

D.A. Schiedler et al. / Tetrahedron 71 (2015) 1448e1465
1453
Table 4
Substrate scope of the translocation method
Entry
Substrate
Product
R3XH
BnSH (equiv)
Yield (%)
1
2
Bu3SnH
0.9
0.1
73
75
(TMS)3SiH
3
4
26
26
Bu3SnH
0.1
0.1
67
44
(TMS)3SiH
5
6
Bu3SnH
0.1
0.1
72
25
(TMS)3SiH
7
Bu3SnH
0.9
0
gave an intractable mixture with no detectable radical addition
product (Eq. 1). However, 33, which bears an N-acyl group, gave
only product 34 in good yield (Eq. 2). It is also notable that aminal
33 has accessible a-amino CeH bonds but none of the a-aminoalkyl
radical addition product 35 was observed. This result suggests that
the N-acyl aminal radical was selectively generated and reacts
Five-membered aminals were also found to participate in the
reaction. Proline and pipecolic acid-derived bicyclic aminals 36 and
37 reacted with methyl acrylate and acrylonitrile to give addition
products 38e41 (Table 5, entries 1e8). The observed diaster-
eoselectivity likely arises from addition to the convex face of the
bicycle. While examining the requirements for the electron-
withdrawing substituent, trifluoroacetyl was found to be a suit-
able activating group as 42 produced the addition product 43. At-
tempts to use substrates bearing carbamate (44a and 44b) or
sulfone (44c) protected aminals failed to produce any of the desired
products, instead giving dehalogenation or decomposition, re-
spectively (entry 11).
without competitive formation of the alternative
a-aminoalkyl
radical. The electron-withdrawing nature of the carbonyl may
stabilize the aminal radical.36
Hexahydropyrimidine and tetrahydroquinoline derived ami-
nals 46 and 47 bearing a 2-iodobenzoyl group (IBz) were pre-
pared. It was envisioned that the IBz substituent could function
as both an electron-withdrawing substituent and the trans-
location group. The desired products 48 and 49 were not ob-
served upon subjection of 46 and 47 to the standard reaction
conditions (entries 12, 13). The absence of the desired reactivity
may be attributable to the conformational constraints of the
stable amide rotamers, which were clearly observable in the NMR
spectra of 46 and 47. It is possible that the favored amide rotamer
may place the IBz group away from the aminal carbon, allowing
time for the radical intermediates to react with Bu3SnH before
the substrate can attain a conformation suitable for the 1,5-H
atom translocation event.
Substrates bearing a tethered radical acceptor were also in-
vestigated and are shown in Table 6. Tetrahydropyrimidinone de-
Scheme 5. Selective formation of aminal radicals.
rivative 50, which bears a tethered a,b-unsaturated ester, yielded

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D.A. Schiedler et al. / Tetrahedron 71 (2015) 1448e1465
Table 5
Scope of the translocation method
Entry
Substrate
Product
R3XH
BnSH (equiv)
Yield (%)
1
2
Bu3SnH
0.9
0.9
46, dr >20:1
(TMS)3SiH
4, dr not determined
3
4
36
Bu3SnH
0.2
0.1
50, dr>20:1
(TMS)3SiH
45, dr 4:1
5
6
Bu3SnH
0.9
0.9
68, dr >20:1
28, dr >20:1
(TMS)3SiH
7
8
37
Bu3SnH
0.2
0.1
68, dr >20:1
(TMS)3SiH
16, dr not determined
9
Bu3SnH
0.1
0.1
69
10
10
(TMS)3SiH
11
Bu3SnH
0.9
0
12
13
(TMS)3SiH
(TMS)3SiH
0.9
0.9
0
0
the bicycle 51 as a single diastereomer. However, isomeric substrate
52, which bears an exocyclic electron-withdrawing group, pro-
duced none of the cyclized product 53, instead giving only the
product of dehalogenation in 82% yield (entries 1e3). The disparity
in the observed reactivity of these substrates may again be attrib-
utable to the conformational preference of the stable amide
rotamers. The quinazolinone-derived aminal 54 cyclized cleanly to
produce 55 (entries 4, 5).

D.A. Schiedler et al. / Tetrahedron 71 (2015) 1448e1465
1455
Table 6
Substrates bearing substitution at the aminal carbon, such as 56
and 57, gave none of the desired spirocyclic aminal containing
products 58 and 59 (entries 6, 7). Again, the lack of desired re-
activity may be attributed to the steric interactions between the
substituent on the aminal carbon and the translocation group,
which disfavor the conformation necessary for the 1,5-H atom
transfer event.
Scope of the translocation method
Entry
Substrate
Product
R3XH
BnSH Yield
(equiv) (%)
A
plausible model explaining the origin of the diaster-
eoselectivity in the formation of aminal 51 is shown in Scheme 6.37
Four possible diastereomeric transition states were considered for
the cyclization (AeD). Structures A and D do not lead to the relative
stereochemistry observed in the major diastereomer of the product
1
2
Bu3SnH
0.1
55, dr
>20:1
(51). The SOMO in structure C is aligned with the
p system of the
amide, and this orientation may lead to stereoelectronic stabiliza-
tion. However, molecular models indicated that C suffers from
unfavorable steric interactions between the ester and the six-
membered ring. In structure B, the SOMO would have less overlap
(TMS)3SiH 0.1
50, dr
>20:1
with the amide
p system, but it presents the alkene radical acceptor
in a more sterically favorable orientation, and we believe this as-
sembly leads to the observed diastereomer. Further experimenta-
tion would be necessary to distinguish between these possible
models.
3
(TMS)3SiH 0.9
0
Seeking to apply the radical translocation method to the total
synthesis of indole alkaloids, we became interested in acyclic N-
formyl aminals bearing indole. Acyclic N-formyl aminals are rare in
the literature, possibly because of their propensity to hydrolyze.
Scheme 7 depicts the known methods for the preparation of acyclic
N-formyl aminals. Aminals 60 were prepared by treatment of N-
substituted formamide derivatives with formaldehyde and a vari-
ety of symmetrical secondary amines (Eq. 1).38 Nucleophilic sub-
stitution of alkyl halide 61 with secondary amines gave aminals 62
in 25e86% yield (Eq. 2).39
4
5
Bu3SnH
0.1
61, dr
1.5:1
(TMS)3SiH 0.9
49, dr
1.5:1
Treatment of N-benzylformamide 63 with formaldehyde and
indole failed to produce the model aminal 64 (Scheme 8, Eq. 1). It
was reasoned that the indole nitrogen was not sufficiently nu-
cleophilic to undergo the necessary condensation with formal-
dehyde. It was postulated that the reactivity of a pre-formed
halide electrophile such as 65 might compensate for the weak
nucleophilicity of indole. To that end, 66 was treated with thionyl
chloride and formaldehyde but none of 65 was isolated (Eq. 2).
Further attempts to form the N-chloromethyl formamide 65 under
a variety of modified reaction conditions were also unsuccessful.
The only isolable product of these reactions was the N,O-hemi-
acetal 67. Formation of 67 likely resulted from the rapid elimina-
tion of chloride to give an N-acyl iminium ion, which was
subsequently trapped by water. The same product was obtained
when 66 was exposed to paraformaldehyde under basic condi-
tions (Eq. 3).
6
7
Bu3SnH
0.9
0
0
(TMS)3SiH 0.9
Scheme 6. Model for the observed diastereoselectivity.

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D.A. Schiedler et al. / Tetrahedron 71 (2015) 1448e1465
Scheme 7. Known methods for the preparation of acyclic N-formyl aminals.
radical acceptor by another means, the product 71 would also be
obtained (Scheme 9).
It was envisioned that protonation and single electron reduction
of the known40 amidine 72 would give intermediate 70. Seeking
conditions suitable for this transformation, 72 was subjected to
reductive conditions in the presence of acrylonitrile (Table 7).
Treatment with Zn metal gave no reaction and LiDBB41 led to de-
composition (entries 1e5). However, treatment with SmI242 in the
presence of stoichiometric camphorsulfonic acid (CSA) gave the
desired product 29 in 31% yield (entry 6). Decreasing the equiva-
lents of SmI2 and adding the reagent slowly resulted in a dramatic
increase in product yield (entry 7). While the reaction proceeded
without the addition of a proton source, yields were substantially
lower and the starting material was not consumed (entry 8). Am-
monium chloride was chosen as the optimal proton source as it is
mild, inexpensive, and generally provided high yields (entry 9). The
amidine reduction method featured several advantages when
compared to the translocation method; it occurred rapidly at room
temperature, required no toxic or foul smelling additives, was op-
erationally simple, and provided improved yields.
With the optimized reaction conditions in hand, a variety of
substrate combinations were evaluated. Quinazolinones are ac-
cessible from the corresponding aminobenzamide derivatives,
possess interesting biological activities,43 and contain the N-acyl
amidine substructure. Reaction of amidine 72 with methyl and tert-
butyl acrylates proceeded smoothly to give 73a and 73b (Scheme
10). Attempts to use methyl vinyl ketone resulted in reduction of
the carbonyl and gave none of the desired radical addition product
(73c). No addition product was observed when allyl alcohol was
used as the radical acceptor (73d). The quinazolinone bearing
a tethered alkene preferentially underwent bimolecular radical
addition with acrylonitrile (74a), tert-butyl acrylate (74b), and
methyl acrylate (74c) rather than unimolecular 5-exo-trig radical
cyclization with the appended alkene.
Scheme 8. Synthesis of indole substituted acyclic N-formyl aminal 68.
The amidine reduction method does not require a benzyl sub-
stituent and substrates bearing N-alkyl (75a, b), N-aryl (76aec), and
unprotected nitrogen (77aec) all participated in the reaction. In
contrast to the translocation method, fully substituted aminals
were prepared in high yield by reductive alkylation of the corre-
sponding amidines (78aec, 79aec). Remarkably, the amidine
bearing a sterically demanding tert-butyl group also reacted in the
desired manner giving an aminal with vicinal fully substituted
carbons (80). Electron-rich arenes are also compatible with the
reaction conditions (81), and no reduction of the arene was
detected.
Reasoning that exposure of 67 to dehydrating conditions might
generate the halide in situ, 67 was treated with PBr3 followed by
subsequent addition of indole (Scheme 8, Eq. 4). Gratifyingly, the
desired acyclic aminal 68 was produced in modest yield. However,
68 failed to produce the desired product 69 when subjected to the
standard radical translocation conditions (Eq. 5). The aminal 68 was
recovered quantitatively.
While the radical translocation strategy had served as an ef-
fective platform to access aminal radical intermediates, a compli-
mentary method that did not require foul smelling or toxic reagents
was desired. Ideally, the starting materials would be easily acces-
sible and would not require a 2-iodobenzyl substituent. Owing to
the success of substrate 26 in the radical translocation reaction,
should aminal radical 70 be generated in the presence of a suitable
Disubstituted acceptors are also reactive in the amidine re-
duction reaction as ethyl crotonate reacted to produce 82 in good
yield, but only modest diastereoselectivity was observed (Table 8,
entry 1). In contrast, intramolecular reactions with di- (83) and

D.A. Schiedler et al. / Tetrahedron 71 (2015) 1448e1465
1457
Scheme 9. Single electron reduction of amidines to generate aminal radicals.
Table 7
and acrylonitrile (102c) (Table 9, entry 1). Amidinium ion 103
reacted to produce fully substituted aminal 104 (entry 2). Pyr-
imidinone (105) and dihydropyrimidinone-derived amidinium ions
(106a, b) also reacted uneventfully to give 107, 108a, and 108b.
Dihydroquinazolinium 109, which does not bear an acyl group on
nitrogen, gave no reaction under the optimized conditions and the
addition product 110 was not obtained (entry 5).
Optimization of the amidine reduction method
Based on the observed reactivity, two plausible mechanisms
were formulated and are detailed in Scheme 11. In mechanism A,
amidine 72 is first protonated and reduced by SmI2 to give the
neutral aminal radical 70. The aminal radical intermediate then
undergoes addition to the alkene, producing free radical in-
termediate 111. Finally, single electron reduction and protonation of
111 give the observed product 73b. Alternatively, the operative
mechanism could involve reduction of the alkene by SmI2 to pro-
duce the radical anion 112, which would then undergo addition to
the amidine 72 to give aminyl radical intermediate 113 (Scheme 11,
mechanism B). Protonation and single electron reduction of 113
would afford the observed product 73b. SmI2 has been shown to
Entry
Conditons
Result
1
2
3
Zn (2.2 equiv), HOAc, rt
Zn (2.2 equiv), HOAc, 80 ꢀC
Zn (2.2 equiv), HOAc, reflux
LiDBB (2.5 equiv), THF, rt
LiDBB (2.5 equiv), CSA (1.1 equiv), THF, rt
SmI2 (6.0 equiv), CSA (1.1 equiv), THF, rt
SmI2 (2.5 equiv), CSA (1.1 equiv), THF, rt
SmI2 (2.5 equiv), THF, rt
No reaction
No reaction
No reaction
Decomposition
Decomposition
31%
90%
57%
99%
4a
5a
6
7a
8a
9a
SmI2 (2.5 equiv), NH4CI (1.1 equiv), THF, rt
a
Slow addition of reductant solution by syringe pump.
reduce a,b-unsaturated esters in some cases and reaction mecha-
trisubstituted (84) olefins proceed with high diastereoselectivity
giving aminals 85 and 86 (entries 2, 3). Amidines that are not
quinazolinones also participate in the reaction. Spirocyclic amidine
87 gave 88 in good yield (entry 4). Norbornene-derived amidine 89
produced 90 as a single diastereomer in nearly quantitative yield
(entry 5). Pyrimidinone 91 underwent alkylation to give aliphatic
aminal 92 (entry 6). Bicyclic amidine 93 reacted to give the fully
substituted aminal 94 in good yield as indicated by 1H NMR anal-
ysis, but could only be isolated in modest yield (entry 7). We
speculate that the product may have decomposed during silica gel
chromatography. Acylated dihydroquinazole 95a gave aminal 96a
in modest yield (entry 8).
As was observed with the translocation method, an electron-
withdrawing group on nitrogen is essential for the desired re-
activity. 3,4-Dihydroquinazoline (95b), DBU (97), and benzimid-
azole (99) gave no reaction under the optimized conditions (entries
8e10). Tosyl protected dihydroquinazole 95c decomposed under
the reaction conditions. This suggested that, as seen with aminal
radicals generated using the translocation method, N-sulfonyl is
not a suitable electron-withdrawing group.
nisms similar to mechanism B have been proposed in the litera-
ture.44 Given that the reactions were carried out in the presence of
a strong acid, it is unlikely that the reaction proceeds through
carbanion intermediates that arise from the reduction of in-
termediate 70.
In order to determine whether the amidine reduction method
was proceeding through the proposed aminal radical intermediate
or by some other pathway, mechanistic investigations were carried
out (Scheme 12). If mechanism A was operative, it was reasoned
that treatment of amidine 114 with SmI2 and a proton source would
give an
a-cyclopropyl aminal radical. Should the radical in-
termediate be sufficiently long lived, products of cyclopropane
fragmentation should be formed.45 As expected, reduction of
amidine 114 in the absence of a radical acceptor produced the cy-
clopropane ring fragmentation product 115 (Eq. 1). Additionally,
treatment of 114 with the standard reaction conditions in the
presence of acrylonitrile yielded bicyclic aminal 11646 along with
addition product 117 (Eq. 2). It should be noted that cyclopropyl
substituents that are not on the amidine carbon are tolerated with
no observable fragmentation (see Scheme 10, 75a).
It was postulated that the reaction proceeded through pro-
tonation of the amidine followed by reduction of the resulting
amidinium ion. If this mechanism was operative, it was reasoned
that amidinium ions would also participate in the reaction.
Dihydroquinazolinone-derived amidinium ion 101 reacted in ex-
cellent yield with methyl acrylate (102a), tert-butyl acrylate (102b),
The use of cyclopropyl substituted acrylate 118 in the reaction
yielded aminal 119 along with reduction product 120 (Eq. 3). It is
possible that the proposed
a-ester radical intermediate is short
lived and undergoes reduction at a rate greater than that of cy-
clopropane fragmentation. If mechanism B was the operative
pathway, then treatment of the alkene with SmI2 in the absence of

1458
D.A. Schiedler et al. / Tetrahedron 71 (2015) 1448e1465
Scheme 10. Scope of the amidine reduction reaction.
an amidine should give products of reduction. However, no reaction
was observed when acrylonitrile, methyl acrylate, tert-butyl acry-
late, or acrylate 118 were exposed to the standard reaction condi-
tions (Eqs. 4e7). These data indicate that mechanism B is not
plausible, and we believe that the reaction proceeds as shown in
mechanism A.
Table 8
Substrate scope of the amidine reduction
3. Conclusion
Entry
Substrate
Product
While aminal radicals have been known in the literature for
more than 20 years, the synthetic utility of these intermediates had
not been reported until recent work from our laboratory. It has
been demonstrated that aminal radical intermediates may be
generated via radical translocation or by reduction of amidines and
amidinium ions. These radicals add to electron poor alkenes to give
products of carbonecarbon bond formation in high chemical yield.
This reactivity has been shown to be effective in both inter-and
intramolecular contexts and can be used to produce fully
substituted aminal stereocenters as well as all carbon quaternary
stereocenters with good diastereocontrol.
1
2
4. Experimental section
4.1. General47
All reactions were carried out under an inert Ar atmosphere in
oven-dried glassware. Flash column chromatography (FCC) was

D.A. Schiedler et al. / Tetrahedron 71 (2015) 1448e1465
1459
Table 8 (continued )
Table 9
Scope of the amidinium reduction
Entry
Substrate
Product
3
Entry
Starting material
Product
4
5
1
2
3
6
7
4
8
5
9
a
CSA was used as the acid.
10
hydride. These reagents were then distilled under vacuum prior to
use. Acrylonitrile was distilled under vacuum prior to use. Bu3SnH
and BnSH were dried over CaH2 and distilled under vacuum prior to
use. Samarium iodide solutions were prepared with THF distilled
from sodium and benzophenone and were stored over an atmo-
sphere of argon with vigorous stirring.48 The concentrations of the
samarium iodide solutions were determined by iodometirc titra-
tion. All other reagents and solvents were used without further
purification from commercial sources. FTIR spectra were measured
using NaCl plates. Multiplicities are abbreviated as follows:
s¼singlet, d¼doublet, t¼triplet, q¼quartet, quin¼quintet,
br¼broad, m¼multiplet. Melting points are uncorrected.
a
CSA was used as the acid.
ꢀ
carried out with SiliaFlash P60, 60 A silica gel. Reactions and col-
umn chromatography were monitored with EMD silica gel 60 F254
plates and visualized with potassium permanganate, iodine, nin-
hydrin, or vanillin stains. Tetrahydrofuran (THF) and methylene
chloride (DCM) were dried by passage through activated alumina
columns. Benzene (PhH) was dried over CaH2, distilled under an
atmosphere of argon, and degassed by three freezeepumpethaw
cycles. Methyl acrylate and tert-butyl acrylate were purified by
washing with aqueous NaOH, drying over MgSO4, and calcium
4.2. Experimental procedures and data of synthetic
intermediates
4.2.1. 3-(2-Iodobenzyl)-1,2,3,4-tetrahydroquinazoline (12). To a so-
lution of 2-iodobenzyliodide49 (0.2301 g, 0.690 mmol) and K2CO3

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D.A. Schiedler et al. / Tetrahedron 71 (2015) 1448e1465
Scheme 11. Possible mechanisms of the amidine reduction reaction.
Scheme 12. Mechanistic investigations.
(0.1819 g, 1.32 mmol) in a mixture of water (0.5 mL, 1.4 M) and THF
(2 mL, 0.35 M) was added 1,2,3,4-tetrahydroquinazoline50
(0.1800 g, 1.34 mmol). The mixture was stirred at room tempera-
ture for 12 h. At this time, TLC indicated the consumption of 2-
iodobenzyliodide. The reaction mixture was concentrated. Flash
column chromatography (9:1 hexanes/EtOAc) gave 12 (0.2202 g,
0.629 mmol, 91%) as a yellow oil.
Data for 12: Rf 0.36 (4:1 hexanes/EtOAc); IR (thin film) 2928,
2847, 1606 cmꢁ1
0.8 Hz, 1H), 7.47 (dd, J¼7.6, 1.6 Hz, 1H), 7.34 (td, J¼7.2, 0.8 Hz, 1H),
;
1H NMR (400 MHz, CDCl3)
d
7.86 (dd, J¼7.6,

D.A. Schiedler et al. / Tetrahedron 71 (2015) 1448e1465
1461
7.06 (td, J¼7.6, 1.2 Hz, 1H), 6.98 (td, J¼7.6, 1.6 Hz, 1H), 6.73 (td,
J¼7.2, 1.2 Hz, 1H), 6.61 (d, J¼8.0 Hz, 1H), 4.13 (s, 2H), 3.94 (s, 2H),
concentrated to give known the adduct 29 (0.0403 g, 0.1383 mmol,
99%) as a colorless oil.
3.79 (s, 2H); 13C NMR (100 MHz, CDCl3)
d 142.8, 141.0, 139.6, 130.4,
128.9, 128.2, 127.7, 127.3, 120.1, 118.4, 115.3, 100.7, 63.0, 61.0, 53.2;
HRMS (TOF MS ESþ) calcd for C15H16N2I [MþH]: 351.0358, found
351.0347.
4.2.4. 2-((2-Iodobenzyl)amino)benzamide (S1). To a solution of 2-
aminobenzamide (0.3647 g, 2.68 mmol) and K2CO3 (1.1117 g,
8.044 mmol) in DMF (4.5 mL, 0.6 M) was added 2-iodobenzyliodide
(1.1087 g, 3.22 mmol). The mixture was stirred at room tempera-
ture for 15 h. At this time, TLC indicated the consumption of 2-
aminobenzamide. The reaction mixture was diluted with EtOAc,
washed with saturated aqueous LiCl, dried over anhydrous MgSO4,
filtered, and concentrated. Recrystallization from MeOH gave S1
(0.9795 g, 2.7 mmol, 100%) as a white solid.
4.2.2. Methyl
3-(3-benzyl-1,2,3,4-tetrahydroquinazolin-2-yl)prop-
anoate (13), methyl 3-(3-benzyl-1,2,3,4-tetrahydroquinazolin-4-yl)
p r o p a n o a t e ( 14 ) , d i m e t h y l 3 , 3 0- ( 3 - b e n z y l - 1, 2 , 3 , 4 -
tetrahydroquinazoline-2,4-diyl)dipropionate (15), and 3-benzyl-
1,2,3,4-tetrahydroquinazoline (16). Representative procedure for the
radical translocation reactions of 12: Compound 12 (0.2030 g,
0.580 mmol) and methyl acrylate (0.16 mL, 1.8 mmol) were dis-
solved in PhH (4.6 mL, 0.13 M) and the mixture was heated to
reflux. A PhH solution (1.2 mL) containing AIBN (0.0198 g,
0.121 mmol) and Bu3SnH (0.31 mL, 1.2 mmol) was added by syringe
pump to the refluxing solution over a period of 1.2 h. After 15 h, the
mixture was cooled to room temperature, concentrated, and re-
dissolved in MeCN. The MeCN solution was washed with hexanes,
concentrated, and purified by flash column chromatography (8:1
hexanes/EtOAc) to give a 1:1 mixture of 13 and 14 (0.0542 g,
0.1748 mmol, 30%) as a colorless oil, 15 (0.0155 g, 0.0391 mmol,
6.7%) as a colorless oil, and 3-benzyl-1,2,3,4-tetrahydroquinazoline
(16) (0.0462 g, 0.206 mmol, 36%).
Data for S1: Rf 0.38 (1:3 hexanes/EtOAc); mp¼160e162 ꢀC; IR
(thin film) 3366, 3190, 1649, 1640, 1619, 1511 cmꢁ1 1H NMR
;
(700 MHz, CDCl3)
d
8.47 (br s, 1H), 7.85 (dd, J¼7.7, 0.7 Hz, 1H), 7.42
(dd, J¼7.7, 1.4 Hz, 1H), 7.33 (d, J¼7.7 Hz, 1H), 7.24e7.28 (m, 2H), 6.95
(td, J¼7.7, 2.1 Hz, 1H), 6.61 (td, J¼7.7, 0.7 Hz, 1H), 6.49 (d, J¼8.4 Hz,
1H), 5.91 (br s, 1H), 5.58 (br s, 1H), 4.39 (s, 3H); 13C NMR (176 MHz,
CDCl3)
115.3, 113.3, 112.6, 98.3, 52.4; HRMS (TOF MS ESþ) calcd for
14H14N2OI [MþH]: 353.0151, found 353.0144.
d 172.2, 150.0, 140.5, 139.5, 133.8, 129.0, 128.6, 128.4, 128.2,
C
4.2.5. 1-(2-Iodobenzyl)-2-phenyl-2,3-dihydroquinazolin-4(1H)-one
(30). To a solution of S1 (0.483 g, 0.137 mmol) and benzaldehyde
(0.02 mL, 0.19 mmol) in DCM (1.4 mL, 0.1 M) was added boron
trilfluoride diethyletherate (0.04 mL, 0.32 mmol). The mixture was
stirred at room temperature for 24 h. The reaction mixture was
then quenched by addition of saturated aqueous NaHCO3, and the
biphasic mixture was separated. The aqueous layer was extracted
with EtOAc. The combined organic layers were dried over anhy-
drous MgSO4, filtered, and concentrated. Flash column chroma-
tography (2:1 hexanes/EtOAc) gave 30 (0.0549 g, 0.125 mmol, 91%)
as a white solid.
Data for 13: Rf 0.28 (4:1 hexanes/EtOAc); IR (thin film) 2920,
1732 cmꢁ1; 1H NMR (700 MHz, CDCl3)
d 7.23e7.34 (m, 5H), 7.04 (t,
J¼7.7 Hz, 1H), 6.86 (d, J¼7.0 Hz, 1H), 6.67 (t, J¼7.7 Hz, 1H), 6.53 (d,
J¼7.7 Hz, 1H), 4.09 (t, J¼7.7 Hz, 1H), 4.03 (br s, 1H), 3.97 (d,
J¼16.8 Hz, 1H), 3.60e3.73 (m, 6H), 2.44e2.53 (m, 2H), 2.04e2.09
(m, 1H), 1.89e1.94 (m, 1H); 13C NMR (176 MHz, CDCl3)
d 174.1, 142.2,
139.4, 128.9, 128.4, 127.9, 127.4, 127.1, 118.3, 117.8, 114.4, 69.4, 55.2,
51.8, 48.1, 30.0, 29.7; HRMS (TOF MS ESþ) calcd for C19H23N2O2
[MþH]: 311.1760, found 311.1770.
Data for 30: Rf 0.31 (1:1 hexanes/EtOAc); mp¼153e155 ꢀC; IR
Data for 14: Rf 0.28 (4:1 hexanes/EtOAc); IR (thin film) 2950,
(thin film) 2918, 1667, 1607, 1489 cmꢁ1; 1H NMR (700 MHz, CDCl3)
1732, 1607 cmꢁ1
;
1H NMR (700 MHz, CDCl3)
d
7.03e7.35 (m, 4H),
d
8.01 (dd, J¼7.7, 1.4 Hz, 1H), 7.82 (dd, J¼7.7, 0.7 Hz, 1H), 7.39 (dd,
7.25e7.27 (m, 1H), 7.05 (td, J¼7.7, 1.4 Hz, 1H), 6.98 (dd, J¼7.7, 1.4 Hz,
1H), 6.71 (td, J¼7.0, 1.4 Hz, 1H), 6.57 (dd, J¼8.4, 1.4 Hz, 1H), 4.33 (d,
J¼11.9 Hz, 1H), 3.90 (br s, 1H), 3.83 (d, J¼13.3 Hz, 1H), 3.81 (dd,
J¼11.9, 1.4 Hz, 1H), 3.63 (s, 3H), 3.56 (d, J¼13.3 Hz, 1H), 3.50 (dd,
J¼11.2, 4.9 Hz, 1H), 2.55 (ddd, J¼16.8, 7.7, 6.3 Hz, 1H), 2.46 (ddd,
J¼14.7, 7.7, 7.7 Hz, 1H), 1.99e2.08 (m, 2H); 13C NMR (176 MHz,
J¼7.7, 1.4 Hz, 2H), 7.32e7.37 (m, 5H), 7.28 (t, J¼7.7 Hz, 1H), 6.97 (td,
J¼7.7, 1.4 Hz, 1H), 6.89 (t, J¼7.7 Hz, 1H), 6.47 (d, J¼8.4 Hz, 1H), 6.32
(s, 1H), 5.97 (d, J¼2.1 Hz, 1H), 4.37 (d, J¼16.8 Hz, 1H), 4.16 (d,
J¼16.8 Hz, 1H); 13C NMR (176 MHz, CDCl3)
d 164.0, 147.3, 139.8,
138.9, 138.0, 134.6, 129.8, 129.3, 129.0, 128.6, 128.3, 127.2, 119.1,
116.5, 113.6, 97.8, 73.4, 57.2; HRMS (TOF MS ESþ) calcd for
CDCl3)
d
174.5, 142.6, 139.3, 129.3, 128.9, 128.3, 127.4, 127.2, 122.9,
C21H18IN2O [MþH]: 441.0464, found 441.0455.
117.9, 114.8, 59.0, 57.1, 56.0, 51.6, 33.0, 30.92; HRMS (TOF MS ESþ)
calcd for C19H23N2O2 [MþH]: 311.1760, found 311.1750.
4.2.6. tert-Butyl 3-(2-iodobenzyl)tetrahydropyrimidine-1(2H)-car-
boxylate (44a). To a solution of 1-(2-iodobenzyl)hexahydropyr-
imidine (0.4342 g,1.44 mmol) in a 1:1 mixture of acetone and water
(9.6 mL, 0.15 M) was added Boc2O (0.3763 g, 1.73 mmol). The
mixture was stirred at room temperature for 24 h. The acetone was
then removed by rotary evaporation and the aqueous mixture was
extracted with EtOAc. The combined extracts were dried over an-
hydrous MgSO4, filtered, and concentrated. Flash column chroma-
tography (8:1 hexanes/EtOAc) gave 44a (0.5229 g, 1.30 mmol, 90%)
as a colorless oil that solidified upon standing.
Data for 15: Rf 0.14 (4:1 hexanes/EtOAc); IR (thin film) 2950,
2851, 1735, 1692, 1493 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 7.23e7.34
(m, 5H), 6.99 (td, J¼8.4, 1.6 Hz, 1H), 6.95 (d, J¼7.2 Hz, 1H), 6.32 (t,
J¼7.6 Hz, 1H), 5.31 (s, 1H), 4.37 (t, J¼6.0 Hz, 1H), 3.94 (d, J¼14.0 Hz,
1H), 3.66 (s, 3H), 3.54 (s, 3H), 3.09 (d, J¼14.0 Hz, 1H), 2.63 (t,
J¼8.0 Hz, 2H), 2.44 (dt, J¼16.8, 6.8 Hz, 1H), 2.24e2.32 (m 1H), 2.09
(q, J¼7.2 Hz, 2H), 2.93 (q, J¼7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d
174.1, 173.7, 143.2, 139.5, 129.1, 128.9, 128.3, 127.1, 126.1, 123.0,
118.4, 114.7, 64.1, 58.0, 51.8, 51.4, 49.1, 32.2, 30.4, 29.4, 27.6; HRMS
(CIþ) calcd for C23H29N2O4 [MþH]: 397.2127, found 397.2129.
Data for 44a: Rf 0.42 (4:1 hexanes/EtOAc); mp¼47e49 ꢀC; IR
(thin film) 2928, 1695 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 7.85 (d,
4.2.3. 3-(3-Benzyl-4-oxo-1,2,3,4-tetrahydroquinazolin-2-yl)propane-
nitrile (29). General reductive alkylation procedure: To a solution of
3-benzylquinazolin-4(3H)-one51 (0.0327 g, 0.1390 mmol), NH4Cl
(0.0089 g, 0.166 mmol), and acrylonitrile (0.05 mL, 0.76 mmol) in
THF (0.46 mL, 0.3 M) was added a THF solution of SmI2 (3.7 mL,
0.35 mmol) via syringe pump over a period of 1 h. At this time, TLC
indicated the consumption of 3-benzylquinazolin-4(3H)-one. The
reaction mixture was diluted with half-saturated aqueous Rochelle
salt. This biphasic mixture was extracted with ethyl acetate. The
combined extracts were dried over MgSO4, filtered, and
J¼7.6 Hz, 1H), 7.47 (d, J¼5.6 Hz, 1H), 7.34 (t, J¼7.2 Hz, 1H), 6.97 (t,
J¼7.6 Hz, 1H), 4.17 (br s, 2H), 3.64 (s, 2H), 3.53 (t, J¼5.2 Hz, 2H), 2.85
(br s, 2H), 1.71 (br s, 2H), 1.43 (s, 9H); 13C NMR (176 MHz, CDCl3)
d
154.7, 140.6, 139.6, 130.0, 128.9, 128.2, 100.5, 65.4, 61.2, 52.3, 43.3,
28.5, 22.9; HRMS (TOF MS ESþ) calcd for C16H24IN2O2 [MþH]:
403.0883, found 403.0896.
4.2.7. Methyl 3-(2-iodobenzyl)tetrahydropyrimidine-1(2H)-carbox-
ylate (44b). To a solution of 1-(2-iodobenzyl)hexahydropyrimidine
(0.7488 g, 1.59 mmol) in DCM (10.5 mL, 0.15 M) was added methyl

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D.A. Schiedler et al. / Tetrahedron 71 (2015) 1448e1465
chloroformate (0.15 mL, 1.94 mmol). The reaction mixture was
stirred at room temperature for 15 h. The reaction mixture was then
washed with brine, dried over anhydrous MgSO4, filtered, and
concentrated. Flash column chromatography (5:1 hexanes/EtOAc)
gave 44b (0.5682 g, 1.58 mmol, 64%) as a colorless oil.
d
172.0, 160.9 (q, J¼35.2 Hz), 142.3, 139.5, 130.9, 128.0, 127.6, 116.5
(q, J¼292.2 Hz), 91.9, 37.1, 36.0, 27.3; HRMS (TOF MS ESþ) calcd for
C
10H14N2OI [Mþ]: 305.0151, found 305.0163.
4.2.11. (2-Iodophenyl)(tetrahydropyrimidin-1(2H)-yl)methanone
(46). To a solution of S3 (0.2096 g, 0.501 mmol) in EtOH (1.7 mL,
0.3 M), 0.08 mL (0.6 mmol) of 30% aqueous NaOH and 0.05 mL
(0.6 mmol) of 36% aqueous formaldehyde solution were added. The
reaction mixture was heated to reflux for 19 h. At this time, the
reaction mixture was concentrated. Flash column chromatography
(19:1 EtOAc/10% NH4OH in MeOH) gave 46 (0.1413 g, 0.447 mmol,
89%) as a white foam.
Data for 44b: Rf 0.29 (4:1 hexanes/EtOAc); IR (thin film) 2928,
1695 cmꢁ1; 1H NMR (700 MHz, CDCl3)
(d, J¼37.1 Hz, 1H), 7.32 (t, J¼7.7 Hz, 1H), 6.96 (br s, 1H), 4.20 (d,
J¼27.3 Hz, 2H), 3.70 (d, J¼16.8 Hz, 3H), 3.63 (s, 2H), 3.57 (br s, 2H),
2.81 (br s, 2H), 1.74e1.65 (m, 2H); 13C NMR (176 MHz, CDCl3)
d
7.83 (d, J¼7.7 Hz, 1H), 7.44
d
155.9, 140.4, 139.5, 130.1, 128.9, 128.1, 100.4, 65.2, 61.1, 52.6, 51.8,
43.8, 22.7; HRMS (TOF MS ESþ) calcd for C13H18N2O2I [MþH]:
361.0413, found 361.0415.
Data for 46: Rf 0.44 (9:1 EtOAc/10% NH4OH in MeOH); IR (thin
film) 2942, 2859, 1628, 1428 cmꢁ1 1H NMR (700 MHz, CDCl3) as
;
4.2.8. 1-(2-Iodobenzyl)-3-tosylhexahydropyrimidine (44c). To a so-
lution of 1-(2-iodobenzyl)hexahydropyrimidine (0.1640 g,
0.543 mmol) in a 2:1 mixture of DCM/H2O (1.65 mL, 0.33 M) were
added K2CO3 (0.1543 g, 1.12 mmol) and TsCl (0.0932 g, 0.489 mmol).
The mixture was stirred at room temperature for 17 h. The reaction
mixture was then diluted with brine and the layers were separated.
The aqueous mixture was extracted twice with DCM and the
combined organic layers were dried over anhydrous MgSO4, fil-
tered, and concentrated. Flash column chromatography (4:1 hex-
anes/EtOAc) gave 44c (0.1930 g, 0.423 mmol, 87%) as a colorless oil.
Data for 44c: Rf 0.57 (3:1 hexanes/EtOAc); IR (thin film) 2860,
a mixture of amide rotamers
d
7.82 (d, J¼7.7 Hz, 1H), 7.37e7.40 (m,
1H), 7.20 (ddd, J¼19.6, 7.7, 1.4 Hz, 1H), 7.08 (td, J¼7.7, 1.4 Hz, 1H),
4.85 (d, J¼12.6 Hz, 0.5H), 4.66 (d, J¼12.6 Hz, 0.5H), 4.18 (d,
J¼13.3 Hz, 0.5H), 4.09e4.13 (m, 0.5H), 4.08 (d, J¼13.3 Hz, 0.5H), 3.70
(ddd, J¼16.1, 8.4, 3.5 Hz, 0.5H), 3.37e3.41 (m, 0.5H), 3.30e3.33 (m,
0.5H), 3.07e3.15 (m, 1.5H), 3.00e3.04 (m, 0.5H), 1.78e1.84 (m,
0.5H), 1.68e1.74 (m, 1H), 1.58e1.63 (m, 0.5H); 13C NMR (176 MHz,
CDCl3) as a mixture of amide rotamers
d 169.2, 168.6, 142.0, 141.7,
139.3, 139.3, 130.6, 130.5, 128.7, 128.6, 127.3, 127.4, 92.5, 92.3, 62.9,
57.1, 64.6, 45.3, 44.8, 41.6, 27.0, 27.0; HRMS (TOF MS ESþ) calcd for
C11H14N2OI [MþH]: 317.0151, found 317.0157.
1651, 1645 cmꢁ1; 1H NMR (700 MHz, CDCl3)
d
7.84 (dd, J¼7.7, 0.7 Hz,
1H), 7.63 (d, J¼8.4 Hz, 2H), 7.37 (d, J¼7.7 Hz, 1H), 7.33 (td, J¼7.0,
0.7 Hz, 1H), 7.30 (d, J¼7.7 Hz, 2H), 6.97 (td, J¼7.7, 1.4 Hz, 1H), 4.01 (s,
2H), 3.78 (s, 2H), 3.25 (s, 2H), 2.76 (t, J¼4.9 Hz, 2H), 2.43 (s, 3H), 1.69
4.2.12. (1,4-Dihydroquinazolin-3(2H)-yl)(2-iodophenyl)methanone
(47). To a solution of 1,2,3,4-tetrahydroquinazoline (0.8921 g,
6.65 mmol) in DCM (22 mL, 0.30 M) were added 2-iodobenzoic
acid (1.9783 g, 7.98 mmol), HOBt (80% in water) (1.3430 g,
7.95 mmol), and DCC (1.6464 g, 7.98 mmol). The mixture was
stirred at room temperature for 16 h. The reaction mixture was
then washed with 1 M aqueous citric acid, saturated aqueous
NaHCO3, and brine. The combined organic layers were then dried
over anhydrous MgSO4, filtered, and concentrated. Flash column
chromatography (2:1 hexanes/EtOAc) gave 47 (2.084 g, 5.72 mmol,
91%) as a white foam.
(br s, 2H); 13C NMR (176 MHz, CDCl3)
d 143.5, 140.4, 139.7, 135.0,
130.8, 129.2, 128.3, 127.6, 101.0, 67.2, 60.3, 50.7, 46.1, 21.7, 21.2;
HRMS (TOF MS ESþ) calcd for C18H21N2O2IS [MþH]: 457.0447,
found 457.0461.
4.2.9. tert-Butyl (3-(2-iodobenzamido)propyl)carbamate (S2). To
a solution of 2-iodobenzoic acid (0.5464 g, 2.20 mmol) in DCM
(11 mL, 0.20 M) were added HOBt (80% in water) (0.4116 g,
2.44 mmol), DCC (0.5063 g, 2.45 mmol), and tert-butyl (3-
aminopropyl)carbamate52 (0.4255 g, 2.44 mmol). The mixture
was stirred at room temperature for 16 h. The reaction mixture was
then filtered through Celite and the solids were rinsed with EtOAc.
The filtrate was washed with 1 M aqueous citric acid, saturated
aqueous NaHCO3, and brine. The combined organic layers were
then dried over anhydrous MgSO4, filtered, and concentrated. Flash
column chromatography (2:1 hexanes/EtOAc) gave S2 (0.6865 g,
1.70 mmol, 77%) as a white solid.
Data for 47: Rf 0.52 (1:1 EtOAc/hexanes); IR (thin film) 3006,
2849, 1633 cmꢁ1 1H NMR (700 MHz, CDCl3) as a mixture of
;
rotamers
d
7.86 (ddt, J¼10.5, 7.7, 0.7 Hz, 1H), 7.41 (dddd, J¼16.1, 7.7,
7.7, 0.7 Hz, 1H), 7.30 (dd, J¼7.7, 1.4 Hz, 0.5H), 7.21 (dd, J¼7.7 2.1 Hz,
0.5H), 7.08e7.14 (m, 2.5H), 6.89 (td, J¼7.7, 0.7 Hz, 0.5H), 6.80 (dt,
J¼16.8, 7.0 Hz, 1H), 6.74 (d, J¼7.7 Hz, 0.5H), 6.70 (d, J¼7.7 Hz, 0.5H),
5.17 (dd, J¼11.2, 3.5 Hz, 0.5H), 5.10 (d, J¼16.8 Hz, 0.5H), 4.88 (dd,
J¼11.9, 3.5 Hz, 0.5H), 4.83 (d, J¼16.8 Hz, 0.5H), 4.48e4.52 (m, 1H),
4.42 (dd, J¼11.2, 3.5 Hz, 0.5H), 4.31 (d, J¼16.1 Hz, 0.5H), 4.20 (br s,
0.5H), 3.95 (br s, 0.5H); 13C NMR (176 MHz, CDCl3) as a mixture of
Data for S2: Rf 0.19 (1:2 hexanes/EtOAc); mp¼112e113 ꢀC; IR
(thin film) 3365, 2917, 1649 cmꢁ1; 1H NMR (700 MHz, CDCl3)
d
7.85
rotamers d 169.4, 169.3, 142.7, 141.9, 141.8, 139.4, 130.7, 130.7, 128.6,
(d, J¼7.7 Hz,1H), 7.35e7.39 (m, 2H), 7.09 (ddd, J¼7.7, 6.3, 2.8 Hz,1H),
6.48 (s, 1H), 6.97 (s, 1H), 4.97 (q, J¼6.3 Hz, 2H), 3.30 (q, J¼6.3 Hz,
2H), 1.76 (quin, J¼6.3 Hz, 2H), 1.42 (s, 9H); 13C NMR (176 MHz,
128.6, 127.9, 127.6, 127.5, 127.5, 127.3, 126.8, 120.7, 120.5, 120.1, 120.1,
117.8, 117.5, 92.7, 92.3, 58.0, 53.3, 47.8, 43.3; HRMS (TOF MS ESþ)
calcd for C15H14N2OI [MþH]: 365.0151, found 365.0155.
CDCl3) d 170.0, 156.9,142.5,140.0,131.2,128.3,128.2, 92.7, 79.6, 37.3,
36.6, 30.3, 28.5; HRMS (TOF MS ESþ) calcd for C15H21N2O3NaI
[MþNa]: 427.0495, found 427.0487.
4.2.13. Ethyl (E)-6-(3-(2-iodobenzyl)tetrahydropyrimidin-1(2H)-yl)-
6-oxohex-2-enoate (52). To a solution of 1-(2-iodobenzyl)hexahy-
dropyrimidine (0.1168 g, 0.556 mmol) in DCM (2.2 mL, 0.25 M)
were added (E)-6-ethoxy-6-oxohex-4-enoic acid53 (0.1059 g,
0.615 mmol), HOBt (80% in water) (0.1078 g, 0.638 mmol), and DCC
(0.1279 g, 0.620 mmol). The mixture was stirred at room temper-
ature for 2 h. The reaction mixture was then filtered, diluted with
EtOAc, washed with 1 M aqueous citric acid, saturated aqueous
NaHCO3, and brine. The combined organic layers were then dried
over anhydrous MgSO4, filtered, and concentrated. Flash column
chromatography (3:2 hexanes/EtOAc) gave 52 (0.0639 g,
0.140 mmol, 25%) as a colorless oil.
4.2.10. 3-(2-Iodobenzamido)propan-1-aminium 2,2,2-
trifluoroacetate (S3). To a suspension of S2 (0.011 g, 0.0272 mmol)
in DCM (0.05 mL, 0.50 M) was added trifluoroacetic acid (0.05 mL,
0.653 mmol). The mixture was stirred at room temperature for 1 h.
The reaction mixture was then concentrated under vacuum to give
S3 (0.0102 g, 0.0244 mmol, 90%) as a colorless oil.
Data for S3: Rf 0.06 (4:1 EtOAc/10% NH4OH in MeOH); IR (thin
film) 2949, 1623 cmꢁ1; 1H NMR (700 MHz, CD3OD)
d
7.91 (dd, J¼8.4,
0.7 Hz, 1H), 7.45 (td, J¼7.7, 1.4 Hz, 1H), 7.37 (dd, J¼7.7, 1.4 Hz, 1H),
7.18 (ddd, J¼8.4, 7.7, 2.1 Hz, 1H), 3.48 (t, J¼7.7 Hz, 2H), 3.12 (t,
J¼7.7 Hz, 2H), 1.97e2.02 (m, 2H); 13C NMR (176 MHz, CD3OD)
Data for 52: Rf 0.42 (1:1 EtOAc/hexanes); IR (thin film) 2922,
1716, 1649, 1435 cmꢁ1; 1H NMR (400 MHz, CDCl3) as a 2:1 mixture

D.A. Schiedler et al. / Tetrahedron 71 (2015) 1448e1465
1463
of amide rotamers
d
7.85 (dd, J¼8.0, 1.2 Hz, 0.6H), 7.81 (d, J¼8.0 Hz,
chromatography (8:1 hexanes/EtOAc) gave 57 (0.1937 g,
0.448 mmol, 39%) as a white foam.
0.4H), 7.31e7.46 (m, 2H), 6.84e7.04 (m, 2H), 5.87 (d, J¼15.6 Hz,
0.4H), 5.71 (dt, J¼15.6, 1.6 Hz, 0.6H), 4.34 (s, 0.8H), 4.18 (q, J¼7.2 Hz,
2H), 4.01 (s, 1.2H), 3.16e3.64 (m, 2H), 3.58 (s, 1.2H), 3.35 (t,
J¼5.6 Hz, 0.8H), 2.84 (t, J¼5.2 Hz, 0.8H), 2.79 (t, J¼5.6 Hz, 1.2H),
2.25e2.60 (m, 2.8H), 2.22e2.26 (m, 1.2H), 1.66e1.75 (m, 2H),
1.25e1.3 (m, 3H); 13C NMR (100 MHz, CDCl3) as a 2:3 mixture of
Data for 57: Rf 0.21 (1:7 EtOAc: hexanes); IR (thin film) 2935,
1629 cmꢁ1; 1H NMR (700 MHz, CDCl3)
d
7.95 (dd, J¼8.4, 1.4 Hz, 1H),
7.83 (dd, J¼8.4, 1.4 Hz, 1H), 7.42 (dd, J¼7.7, 1.4 Hz, 1H), 7.28e7.32 (m,
2H), 6.97 (td, J¼7.7, 0.7 Hz, 1H), 6.86 (td, J¼7.7, 0.7 Hz, 1H), 6.65 (dd,
J¼7.7, 0.7 Hz, 1H), 5.71 (ddd, J¼10.5, 7.0, 7.0 Hz, 1H), 5.46 (d,
J¼15.4 Hz, 1H), 4.30e4.97 (m, 2H), 4.51 (dd, J¼9.1, 3.5 Hz, 2H), 4.10
(d, J¼15.4 Hz,1H), 2.00e2.04 (m, 2H), 1.89e1.95 (m, 1H), 1.71 (dddd,
J¼23.1, 10.5, 5.6, 3.5 Hz, 1H), 1.41e1.47 (m, 1H), 1.32e1.38 (m, 1H);
amide rotamers
d 170.5, 170.0, 166.6, 174.8, 140.0, 139.9, 139.6,
130.5, 129.4, 129.0, 128.4, 122.2, 121.8, 100.7, 66.7, 63.1, 62.3, 61.5,
60.4, 60.3, 53.0, 51.8, 45.4, 42.2, 31.5, 31.1, 27.6, 27.5, 24.0, 23.8,
14.4; HRMS (TOF MS ESþ) calcd for C19H26N2O3I [MþH]: 457.0988,
found 457.0971.
13C NMR (176 MHz, CDCl3)
d 162.4, 145.2, 139.6, 139.2, 137.8, 133.7,
129.3, 128.9, 128.9, 128.7, 119.3, 116.7, 115.5, 115.2, 98.8, 68.8, 52.4,
33.2, 32.4, 24.1; HRMS (TOF MS ESþ) calcd for C20H22N2OI [MþH]:
433.0777, found 433.0789.
4 . 2.14 . Et hyl ( E ) - 6 - ( 1- ( 2 - i od o b e n z yl ) - 4 - o x o- 1, 2, 3, 4 -
tetrahydroquinazolin-2-yl)hex-2-enoate (56). To a solution of S1
(1.3201 g, 3.75 mmol) and ethyl (E)-7-oxohept-2-enoate54
(0.7731 g, 4.54 mmol) in DCM (37 mL, 0.1 M) was added boron
trifluoride diethyletherate (0.95 mL, 7.56 mmol). The mixture was
stirred at room temperature for 21 h. The reaction mixture was
then quenched by addition of saturated aqueous NaHCO3, and the
biphasic mixture was separated. The aqueous layer was extracted
with EtOAc, the combined organic layers were dried over anhy-
drous MgSO4, filtered, and concentrated. Flash column chroma-
tography (1:1 hexanes/EtOAc) gave 56 (0.9909 g,1.96 mmol, 52%) as
a white foam.
4.2.17. N-(Hydroxymethyl)-N-(2-iodobenzyl)formamide
a
(67). To
solution of known N-(2-iodobenzyl)formamide55 (224 mg,
0.857 mmol) in THF (4.3 mL) were added paraformaldehyde (31 mg,
1.03 mmol) and K2CO3 (142 mg, 1.03 mmol) at room temperature
and the reaction was monitored by TLC. After 12 h, the reaction
mixture was diluted with Et2O, washed with brine, and dried over
NaSO4. Purification by flash column chromatography (2:1 EtOAc/
hexanes) afforded 67 (168 mg, 67%) as a colorless oil.
Data for 67: Rf 0.25 (2:1 EtOAc/hexanes); IR (thin film) 3356,
2921,1667, 1438,1403,1013 cmꢁ1; 1H NMR (400 MHz, CDCl3),
d 8.38
Data for 56: Rf 0.15 (1:1 EtOAc/hexanes); IR (thin film) 2937,
(d, J¼21.2 Hz, 1H), 7.89 (ddd, J¼14, 8, 1.2 Hz, 1H), 7.38 (dtd, J¼20, 7.6,
1.2 Hz, 1H), 7.29 (td, J¼5.6, 2 Hz, 1H), 7.04 (dtd, J¼18.8, 7.6, 1.6 Hz,
1H), 4.82 (d, J¼3.6 Hz, 2H), 4.75 (s, 1H), 4.59 (s, 1H), 1.68 (br s, 1H);
1714, 1667, 1607, 1491 cmꢁ1; 1H NMR (700 MHz, CDCl3)
d 8.00 (br s
1H), 7.93 (d, J¼7.7 Hz, 1H), 7.86 (d, J¼7.7 Hz, 1H), 7.34 (d, J¼7.7 Hz,
1H), 7.21e7.31 (m, 2H), 6.99 (t, J¼7.0 Hz, 1H), 6.83e6.89 (m, 2H),
6.54 (d, J¼7.7 Hz, 1H), 5.77 (d, J¼16.1 Hz, 1H), 4.60e4.64 (m, 2H),
4.20 (d, J¼16.1 Hz, 1H), 4.14 (q, J¼7.0 Hz, 2H), 2.13e2.21 (m, 2H),
1.85e1.91 (m, 1H), 1.71e1.76 (m, 1H), 1.57e1.64 (m, 1H), 1.48e1.54
13C NMR (176 MHz, CDCl3)
d 164.9, 163.2, 140.1, 139.7, 138.5, 137.8,
129.9, 129.6, 129.4, 129.2, 128.9, 128.8, 99.2, 98.6, 71.8, 67.6, 55.1,
49.3; HRMS (TOF MS ESþ) calcd for [MþH]: C9H10INO2 291.9836,
found 291.9835.
(m, 1H), 1.25 (t, J¼7.0 Hz, 3H); 13C NMR (176 MHz, CDCl3)
d 166.6,
164.5, 148.1, 146.2, 139.8, 138.2, 134.3, 129.5, 128.8, 128.7, 122.1,
118.8, 117.1, 114.0, 98.2, 70.0, 60.3, 58.2, 33.7, 31.7, 23.0, 14.4; HRMS
(TOF MS ESþ) calcd for C23H26N2O3I [MþH]: 505.0988, found
505.0979.
4.2.18. N-((1H-Indol-1-yl)methyl)-N-(2-iodobenzyl)formamide
(68). To a solution of N,O-acetal 67 (38 mg, 0.131 mmol) in DMF
(0.53 mL) at 0 ꢀC was added dropwise PBr3 (0.01 mL, 0.053 mmol).
After 2.5 h at 0 ꢀC, another portion of PBr3 (0.01 mL, 0.053 mmol)
was added and allowed to slowly warm to room temperature. After
4.5 h, indole (15 mg, 0.131 mmol) was added and was stirred
overnight at room temperature. The reaction mixture was diluted
with Et2O and washed with water. The aqueous layer was extracted
with Et2O and the combined organic layers were dried over Na2SO4.
Purification by flash column chromatography (2:1 hexanes/EtOAc)
afforded 68 (13.6 mg, 27%) as a colorless oil.
4.2.15. 2-(Pent-4-en-1-yl)-2,3-dihydroquinazolin-4(1H)-one
(S4). To a solution of 2-aminobenzamide (0.1111 g, 0.677 mmol)
and hex-5-enal (0.4162 g, 4.24 mmol) in EtOH (6.3 mL, 0.6 M) was
added 0.10 mL (0.75 mmol) of 30% aqueous NaOH. The mixture was
heated at reflux for 24 h. The reaction mixture was then diluted
with brine and the biphasic mixture was separated. The aqueous
layer was extracted with EtOAc. The combined organic layers were
dried over anhydrous MgSO4, filtered, and concentrated. Flash
column chromatography (3:2 hexanes/EtOAc) gave S4 (0.0756 g,
0.350 mmol, 8%) as a white solid.
Data for 68: Rf (3:2 hexanes/EtOAc); IR (thin film) 2918, 2850,
1659, 1437, 1014 cmꢁ1
;
1H (700 MHz, CDCl3),
d
8.55 (d, J¼194 Hz,
1H), 8.15 (d, J¼29 Hz, 1H), 7.89 (dd, J¼36, 1.4 Hz, 1H), 7.62 (dd,
J¼140, 7.4 Hz, 1H), 7.41 (m, 2H), 7.31 (m, 1H), 7.27 (m, 1H), 7.19 (m,
3H), 7.13 (m, 1H), 7.03 (dtd, J¼49, 15.3, 7.4 Hz, 1H), 4.68 (s, 1H), 4.57
Data for S4: Rf 0.23 (1:1 EtOAc/hexanes); mp¼137e139 ꢀC; IR
(thin film) 2852, 1634 cmꢁ1; 1H NMR (700 MHz, CDCl3)
d
7.88 (dd,
(d, J¼6.7 Hz, 2H), 4.34 (s, 1H); 13C (176 MHz, CDCl3)
d 163.6, 163.0,
J¼7.7, 1.4 Hz, 1H), 7.31 (ddd, J¼8.4, 7.7, 2.1 Hz, 1H), 6.59 (ddd, J¼7.7,
7.7, 0.7 Hz, 1H), 6.67 (d, J¼7.7 Hz, 1H), 6.13 (br s, 1H), 5.79 (ddd,
J¼9.8, 6.3, 6.3 Hz, 1H), 5.00e5.06 (m, 2H), 4.90 (td, J¼5.6, 0.7 Hz,
1H), 4.20 (br s, 1H), 2.14 (q, J¼7.0 Hz, 2H), 1.78 (ddd, J¼7.7, 7.7,
140.1, 139.6, 138.2, 138.0, 136.6, 136.4, 129.6, 129.1, 128.6, 128.5,
128.5, 128.4, 126.7, 126.3, 124.6, 124.1, 122.8, 122.6, 120.3, 120.1,
119.6, 118.6, 111.5, 111.1, 110.6, 110.1, 98.7, 98.5, 54.6, 49.8, 43.0, 36.4;
HRMS (TOF MS ESþ) calcd for [MþH]: C17H15IN2O 391.0290, found
391.0307.
5.6 Hz, 2H), 1.51e1.61 (m, 2H); 13C NMR (176 MHz, CDCl3)
d 165.4,
147.5, 137.7, 134.0, 128.8, 119.6, 116.0, 115.8, 114.9, 65.4, 35.0, 33.3,
23.3; HRMS (TOF MS ESþ) calcd for C13H17N2O [MþH]: 217.1341,
found 217.1342.
4.2.19. 3-Tosyl-3,4-dihydroquinazoline (95c). To a solution of 3,4-
dihydroquinazoline (0.0748 g, 0.556 mmol) and NEt3 (0.12 mL,
0.86 mmol) in THF (1.4 mL, 0.4 M) was added TsCl (0.1201 g,
0.630 mmol). The mixture was stirred at room temperature for
23 h. The reaction mixture was then diluted with EtOAc, washed
with saturated brine, dried over anhydrous MgSO4, filtered, and
concentrated. Flash column chromatography (4:1 hexanes/EtOAc)
gave 95c (0.0968 g, 0.338 mmol, 60%) as a white solid.
4.2.16. 3-(2-Iodobenzyl)-2-(pent-4-en-1-yl)-2,3-dihydroquinazolin-
4(1H)-one (57). To a solution of S4 (0.2487 g, 1.15 mmol) and NaOH
(0.0984 g, 2.46 mmol) in THF (4 mL, 0.3 M) was added 2-
iodobenzyliodide (0.4478 g, 1.30 mmol). The mixture was heated
to reflux for 15 h. After cooling to room temperature, the reaction
mixture was diluted with EtOAc, washed with brine, dried over
anhydrous MgSO4, filtered, and concentrated. Flash column
Data for 95c: Rf 0.58 (2:1 EtOAc/hexanes); IR (thin film) 2917,
2849, 1620, 1597, 1350 cmꢁ1 1H NMR (700 MHz, CDCl3)
; d 7.88 (s,

1464
D.A. Schiedler et al. / Tetrahedron 71 (2015) 1448e1465
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(e) Vieira, A. J. S. C.; Steenken, S. J. Am. Chem. Soc. 1987, 109, 7441e7448; (f)
Novais, H. M.; Telo, J. P.; Steenken, S. J. Chem. Soc., Perkin Trans. 2 2002,
1412e1417; (g) Vieira, A. J. S. C.; Steenken, S. J. Phys. Chem. 1991, 95, 9340e9346;
(h) Cullis, P. M.; Malone, M. E.; Podmore, I. D.; Symons, M. C. R. J. Phys. Chem.
1995, 99, 9293e9298; (i) Vinchurkar, M. S.; Rao, B. S. M.; Mohan, H.; Mittal, J. P.
J. Chem. Soc., Perkin Trans. 2 1999, 609e617; (j) Pramod, G.; Mohan, H.; Manoj,
P.; Manojkumar, T. K.; Manoj, V. M.; Mittal, J. P.; Aravindakumar, C. T. J. Phys.
Org. Chem. 2006, 19, 415e424.
1H), 7.79 (d, J¼9.1 Hz, 1H), 7.38 (d, J¼7.7 Hz, 1H), 7.19e7.23 (m,
2H), 7.12 (td, J¼7.7, 2.1 Hz, 1H), 6.92 (dd, J¼7.0, 0.7 Hz, 1H), 4.62 (s,
2H), 2.45 (s, 3H); 13C NMR (176 MHz, CDCl3)
d 145.6, 141.1, 138.6,
133.4, 130.5, 129.1, 127.8, 127.5, 126.3, 126.0, 120.4, 43.7, 21.8;
HRMS (TOF MS ESþ) calcd for C15H15N2O2S [MþH]: 287.0854,
found 287.0840.
13. (a) Marcinek, A.; Zielonka, J.; Gebicki, J.; Gordon, C. M.; Dunkin, I. R. J. Phys.
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4.2.20. 2-(Pent-4-en-1-yl)-1,2,3,4-tetrahydroquinazoline (S11). To
a solution of hex-5-enal56 (0.2041 g, 2.08 mmol) and NH4Cl
(0.0185 g, 0.346 mmol) in EtOAc (10 mL, 0.1 M) was added 2-
aminobenzylamine (0.2109 g, 1.7262 mmol). The mixture was
stirred at room temperature for 0.5 h. At this time, TLC indicated the
consumption of 2-aminobenzylamine. The reaction mixture was
filtered through Celite and was then concentrated. A light yellow oil
resulted. Flash column chromatography (3:1 hexanes/EtOAc) gave
S11 (0.2501 g, 1.236 mmol, 72%) as a colorless oil.
ꢁꢂ
ꢂ
17. (a) Yao, C.; Cuadrado-Peinado, M. L.; Polasek, M.; Turecek, F. Angew. Chem., Int.
Et. 2005, 44, 6708e6711; (b) Cabrera-Rivera, F. A.; Ortíz-Nava, C.; Escalante, J.;
Data for S11: Rf 0.16 (1:1 hexanes/EtOAc); IR (thin film) 2928,
2849,1607 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
7.01 (td, J¼8.0, 0.4 Hz,
ꢁ
ꢁ
^
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J¼8.0 Hz, 1H), 5.83 (dddd, J¼23.6, 10.0, 6.4, 6.4 Hz, 1H), 4.97e5.07
(m, 2H), 4.11e4.16 (m, 2H), 3.95 (d, J¼16.8 Hz, 1H), 3.88 (br s, 1H),
2.13 (q, J¼6.8 Hz, 2H), 1.54e1.66 (m, 4H); 13C NMR (100 MHz, CDCl3)
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(o) Mizutani, M.; Inagaki, F.; Nakanishi, T.; Yanagihara, C.; Tamai, I.; Mukai, C.
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d
143.8, 138.4, 127.3, 126.3, 121.7, 118.1, 115.1, 66.9, 46.7, 46.7, 36.1,
33.7, 24.3; HRMS (EIþ) calcd for C13H18N2 [Mþ]: 202.14700, found
202.14632.
Acknowledgements
The authors acknowledge financial support from Oregon State
University.
Supplementary data
Depiction of 1H and 13C NMR spectra of all new compounds.
Supplementary data associated with this article can be found in the
online version, at http://dx.doi.org/10.1016/j.tet.2014.12.067.
22. Urry, W. H.; Juveland, O. O. J. Am. Chem. Soc. 1958, 80, 3322e3328.
23. For details, see the Supplementary data.
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26. The values reported in Table 1 are isolated yields.
27. Because the isomeric addition products 13 and 14 were inseparable by flash
column chromatography, we have reported combined yields. The ratio of 13/14
was approximately 1:1 in all cases.
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