Direct imine acylation for molecular diversity in heterocyclic synthesis

Article abstract of DOI:10.1021/jo402768r

Imines and carboxylic acids have been directly coupled using propylphosphonic acid anhydride and NEt(i-Pr)₂ to give N-acyliminium ions, which were intramolecularly trapped with oxygen, nitrogen, sulfur, and carbon nucleophiles to provide a wide range of structurally diverse heterocycles.

Full text of DOI:10.1021/jo402768r

Article
pubs.acs.org/joc
Direct Imine Acylation for Molecular Diversity in Heterocyclic
Synthesis
William P. Unsworth, Graeme Coulthard, Christiana Kitsiou, and Richard J. K. Taylor*
Department of Chemistry, University of York, Heslington, York YO10 5DD, U.K.
S
* Supporting Information
ABSTRACT: Imines and carboxylic acids have been directly
coupled using propylphosphonic acid anhydride and NEt(i-
Pr)2 to give N-acyliminium ions, which were intramolecularly
trapped with oxygen, nitrogen, sulfur, and carbon nucleophiles
to provide a wide range of structurally diverse heterocycles.
Scheme 1. Direct Imine Acylation (DIA)
INTRODUCTION
■
Heterocycles are important structures in the pharmaceutical,
agrochemical, and fine chemical industries.1,2 Much recent
attention has focused on diversity-oriented synthesis3−5 to
expand the variety of structures, including heterocycles,
populating unexplored “chemical space” to aid the discovery
of novel lead compounds.6
The chemistry of N-acyliminium ions is well established,7−9
and the formation of N-acyliminium ions by the direct acylation
of imines with acid halides10−21 and anhydrides22−24 has some
precedent. However, apart from a single example,25 previous to
our recent disclosures,26,27 the direct acylation of imines with
carboxylic acids was not known. We reported26 that imines can
be coupled, using propylphosphonic acid anhydride (T3P) and
NEt(i-Pr)2,28 to benzoic acids in a direct imine acylation (DIA)
reaction to generate N-acyliminium ions, which were then
trapped intramolecularly with a range of nucleophilic ortho
substituents on the benzoic acids (Scheme 1, eq 1). This
provided a range of polycyclic heterocycles, and the method-
ology was applied to the synthesis of the natural product
evodiamine. However, this methodology was limited to benzoic
acids containing nucleophilic heteroatoms in the ortho position.
To date, only a single example of DIA using an aliphatic
carboxylic acid has been reported.27 We considered that the
direct coupling of imines and aliphatic carboxylic acids
containing nucleophiles, or pronucleophiles, would allow access
to a far greater variety of heterocyclic structures using this
simple coupling procedure.
structural diversity to be generated via carbon−carbon bond
formation (Scheme 1, eq 3).
RESULTS AND DISCUSSION
■
To establish the validity of the DIA protocol with aliphatic
acids, we investigated the reaction of imine 1a with hydroxy
acid 2a and its TBDMS-protected analogue 2b (Scheme 2).
The reaction of hydroxy acid 2a led to the formation of the
desired heterocycle 3a, but in low yield. This appeared to be
due to competing O-acylation of the hydroxy acid; note that
this was not a problem in our previous work, when ortho-
Herein we report results which establish that DIA method-
ology has an extremely wide scope and is applicable to aliphatic
carboxylic acids containing oxygen, nitrogen, and sulfur
nucleophiles (Scheme 1, eq 2). Of particular note is the use
of aliphatic acids containing carbon pronucleophiles such as
active methylenes, aromatic groups, and alkenes, enabling
Received: December 13, 2013
Published: January 17, 2014
© 2014 American Chemical Society
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imines; however, unsubstituted imine 1b (which exists largely
as a trimer31) was a suitable substrate (entry 3), showing that
imines which are prone to oligomerization are compatible. The
five-membered-ring imine 1c and tetrahydroisoquinoline
derivative 1d both reacted successfully, giving products 3e,f
(entries 4 and 5). Precedent for N-acyliminium chemistry using
acyclic precursors is extremely sparse due to their propensity to
hydrolyze.11 However, the use of DIA conditions allowed the
acyclic imine 1e to be effectively employed (entry 6); in this
case, the use of anhydrous triflic acid, rather than SnCl2·2H2O,
reduced unwanted hydrolysis, promoting a one-pot depro-
tection and cyclization. In this example, chloroform, rather than
CH2Cl2, was used to effect cyclization because it has a higher
reflux temperature and the analogous process in CH2Cl2 (either
at room temperature or 45 °C) was low yielding. The N-
acylation was also performed in chloroform, to avoid having to
perform a solvent switch. It is noteworthy that the T3P
coupling can be performed in a number of solvents with little
impact on the efficiency of the process; high-yielding DIA
reactions performed in toluene, CH2Cl2, chloroform, and THF
have all been reported, previously26,27 and herein. This
flexibility in terms of the solvent for the N-acylation is
important in examples in which additional reagents are required
to effect cyclization (e.g. Table 4), as the solvent that is most
compatible with the requisite additives can be used. Either
CH2Cl2 or chloroform was used in the majority of subsequent
examples for reasons of convenience, as they could be used as
obtained commercially with no additional drying. The stereo-
chemical assignments of the major diastereoisomers shown are
based on NMR analysis, on literature precedent, and by analogy
to our previous work.27,29,32,33 This direct imine acylation with
aliphatic carboxylic acids gives rise to a range of previously
unreported structures, the core of which is present in
compounds which have recently found use as herbicides.34
The analogous DIA process using amine-containing coupling
partners was investigated next (Table 2). Three imines were
reacted with commercially available N-Boc or N-Cbz-protected
amino acids. As with the oxygen variant, following the T3P
coupling, an aqueous workup was carried out. This was
followed by cleavage of the N-protecting group (using TFA in
CH2Cl2 for Boc cleavage or H2/Pd(OH)2 in MeOH for Cbz
cleavage), resulting in cyclization and formation of the expected
nitrogen-containing heterocycles in excellent yields. Both α-
and β-amino acids were suitable substrates (entries 1 and 2),
and substitution on the amino acid was fully compatible (entry
3). It was found that secondary amines were effective
nucleophiles, as evidenced by the use of N-Boc-(S)-proline
(entry 4). Other imines were compatible with the procedure,
including β-carboline 1f (entry 5). Note that, in all of these
examples, the N-acylation was performed at reflux, rather than
at room temperature. This is not because the N-acylation is
slower in this system but because the higher temperature also
promotes partial cyclization before protecting group cleavage. It
was found that this higher temperature led to higher overall
yields for the two-step sequence in comparison to the case
where the coupling was carried out at room temperature. The
assigned syn stereochemistry of the major diastereoisomers of
5c,d is based on analogy with the work of Liebscher35 and, for
5d, a NOESY correlation.
Scheme 2. DIA with Aliphatic Carboxylic Acids
substituted benzoic acids were used due to their reduced
nucleophilicity. To avoid O-acylation, the silyl-protected acid
2b was coupled with 1a and following aqueous workup a
mixture of products was obtained, presumably arising from the
reaction of the N-acyliminium ion with water in the workup.
The unpurified product mixture was then treated with SnCl2·
2H2O29,30 in CH2Cl2 at room temperature, which resulted in
concomitant silyl cleavage and cyclization, affording product 3a
in 68% yield, a significant improvement over the unprotected
variant.
The scope of this improved protocol was then explored
(Table 1). The coupling of imine 1a with TBDMS-protected 3-
hydroxypropanoic acid 2c and methyl-substituted acid 2d
provided the required heterocycles in good yield (Table 1,
entries 1 and 2). We also investigated the range of imines
tolerated in the DIA reaction (Table 1). The majority of the
imines tested as DIA substrates are stable, nonenolizable
Table 1. DIA and Intramolecular Cyclization with Oxygen
b
Nucleophiles
The sulfur variant of this DIA sequence is extremely efficient,
affording S-containing heterocycles in high yields in a one-pot
procedure with no protecting group required on the thiol
(Table 3). The reactions proceeded at room temperature and
a
b
No intermediate workup carried out. The following reaction
conditions were used in this reaction: (i) T3P, NEt(i-Pr)2, CHCl3,
70 °C, 1 h; (ii) TfOH, room temperature, 1 h (one pot).
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Table 2. DIA and Intramolecular Cyclization with Nitrogen
Nucleophiles
Table 3. DIA and Intramolecular Cyclization with Sulfur
Nucleophiles
are both reliable and high-yielding in comparison with known
syntheses of related heterocyclic systems.36 Variation in the
sulfur-containing carboxylic acid is tolerated, as 3-mercapto-
propionic acid 6a, N-acetyl-L-cysteine 6b, and thioglycolic acid
6c (entries 1−4) were suitable substrates. The reactions of
ketone-derived imines 1g,h (entries 3 and 4) are particularly
noteworthy, as these imines do not undergo DIA in any of the
other reaction systems tested (i.e. carboxylic acids bearing O-,
N-, or C-nucleophiles). This suggests that an alternative
mechanism, which was proposed in our previous communica-
tion,26 is likely to operate, whereby the nucleophilic thiol
attacks the imine before N-acylation in these examples. 3,4-
Dihydro-β-carboline 1f (entry 5) was also a suitable imine
substrate, as was the acyclic imine N-benzylidenemethylamine
1e, which gave the adduct 7f in 93% yield (entry 6). The
thiazolidinone scaffold is important in medicinal chemistry and
present in numerous biologically active compounds,37 and this
DIA methodology allows ready access to structurally diverse
thiazolidinone-containing substructures.
The value of this methodology is further enhanced by the
ability to form C−C bonds by trapping the N-acyliminium ion
with various carbon-centered nucleophiles (Table 4). In these
reactions a one-pot process was achieved by using a Lewis acid
to effect cyclization after the coupling (Table 4). Carboxylic
acids tethered to a diester or diketone (entries 1 and 2) were
used to generate an N-acyliminium ion, which cyclized upon
the addition of AlCl3. Keen to extend the scope of carbon
nucleophiles, we investigated electron-rich aromatic systems,
including 3,4-dimethoxyphenyl, indole, pyrrole, and dimethox-
ynaphthyl systems (entries 3−6). These substrates also
provided the expected products in good to excellent yields,
with BF3·OEt2 used to effect cyclization.
Finally, we explored the possibility that carboxylic acids
containing olefins could be successfully utilized and were
pleased to find that an alkene (entry 7) and an allylsilane (entry
8) were compatible, using either TFA or BF3·OEt2 as the
activating agent. The core substructures of 9a−c are prevalent
in a number of natural products,38−40 and the heterocyclic core
of 9e is present in aldose reductase inhibitors.41 Thus, DIA of
imines with aliphatic carboxylic acids, and subsequent
cyclization, can be considered to be of high importance in
the synthesis of medicinally important frameworks.
In conclusion, we have demonstrated that a range of imines
can be directly coupled with carboxylic acids using T3P and
NEt(i-Pr)2 to give N-acyliminium ions which can be intra-
molecularly trapped with oxygen, nitrogen, sulfur, and carbon
nucleophiles. These reactions enable a range of diverse
heterocyclic structures to be generated. Investigations into
asymmetric variants are ongoing, as are applications in target
synthesis.
EXPERIMENTAL SECTION
■
Preparation of Substrates for the DIA Reactions. The
following substrates were commercially available and used as supplied:
N-benzylidenemethylamine 1e, the amino acids 4a−d, the thioacids
6a−c, (3,4-dimethoxyphenyl)acetic acid 8c, 3-indoleacetic acid 8d, and
4,7-dimethoxy-1-naphthoic acid 8f. The following substrates were
prepared according to literature procedures: imines 1a−d,26 Me-
isoquinoline imine 1g,42 Ph-isoquinoline imine 1h,43 TBDMS-
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4-Acetyl-5-oxohexanoic Acid (8b). The title compound was
prepared by modified literature procedures. According to the
procedure of Shrout and Lightner,48 ethyl acrylate (2.00 g, 2.16 mL,
20.0 mmol), 2,4-pentanedione (8.00 g, 8.22 mL, 79.9 mmol), and
K2CO3 (1.38 g, 9.99 mmol) were stirred together at 37 °C for 20 h.
The mixture was filtered through a sintered-glass funnel, and the solids
were washed with CH2Cl2 (2 × 10 mL). The filtrate was concentrated
in vacuo until excess 2,4-pentanedione was removed (judged by TLC).
This provided ethyl 4-acetyl-5-oxohexanoate (3.18 g, 79%) as a pale
yellow liquid: Rf 0.80 (ethyl acetate); νmax (thin film)/cm−1 2984,
2940, 1727, 1699, 1608, 1421, 1359, 1249, 1182, 1152, 1027; δH (400
MHz, CDCl3) data for keto form 3.74 (1H, t, J = 6.9), 4.14 (2H, q, J =
7.0), 2.33−2.27 (2H, m), 2.21 (6H, s), 2.19−2.12 (2H, m), 1.26 (3H,
t, J = 7.0), data for enol form 16.78 (1H, s), 4.15 (2H, q, J = 7.2),
2.63−2.57 (2H, m), 2.42−2.36 (2H, m), 2.17 (6H, s), 1.27 (3H, t, J =
7.2); HRMS (ESI) m/z calcd 201.1121 for C10H17O4 (MH+), found
201.1113. Ethyl 4-acetyl-5-oxohexanoate (500 mg, 2.50 mmol) was
dissolved in THF/H2O (1/1, 10 mL) and stirred at room temperature.
Concentrated H2SO4 (1.25 mL) was added and the reaction mixture
stirred at room temperature for 14 h. The reaction mixture was diluted
with water (10 mL) and extracted with CH2Cl2 (3 × 10 mL). The
combined organic phases were dried (MgSO4), filtered, and
concentrated to give the crude material. Purification by column
chromatography (1/1 petroleum ether/ethyl acetate) gave 4-acetyl-5-
oxohexanoic acid (8b; 224 mg, 52%) as a clear, colorless oil: Rf 0.25
(ethyl acetate); δH (400 MHz, CDCl3) data for keto form 3.76 (1H, t,
J = 7.0), 2.41−2.35 (2H, m), 2.22 (6H, s), 2.19−2.12 (2H, m), data for
enol form 16.78 (1H, s), 2.66−2.59 (2H, m), 2.50−2.43 (2H, m), 2.18
(6H, s); HRMS (ESI) m/z calcd 173.0808 for C8H13O4 (MH+), found
173.0812.
Table 4. DIA and Intramolecular Cyclization with Carbon
Nucleophiles
1H-Pyrrol-1-ylacetic Acid (8e). The title compound was prepared
using a modified procedure of Mitchell and co-workers;49 glycine ethyl
ester hydrochloride (2.50 g, 17.9 mmol) and sodium acetate (2.45 g,
29.9 mmol) were placed in a round-bottomed flask. Water (12.5 mL)
and acetic acid (25 mL) were then added, followed by 2,5-
dimethoxytetrahydrofuran (2.37 g, 2.32 mmol, 17.9 mmol). The
resulting mixture was stirred at 100 °C for 4 h and then cooled. The
reaction mixture was poured into water (50 mL) and washed with
EtOAc (30 mL). The aqueous phase was neutralized with solid
Na2CO3 and extracted with EtOAc (2 × 30 mL). The combined
organic phases were washed with water (50 mL) before being dried
(MgSO4), filtered, and concentrated to give a crude material which
was purified by column chromatography (4/1 petroleum ether/ethyl
acetate) to give ethyl 1H-pyrrol-1-ylacetate (1.79 g, 65%) as a brown
oil: Rf 0.56 (4/1 petroleum ether/ethyl acetate); νmax (thin film)/cm−1
2985, 2939, 1748, 1500, 1297, 1188, 1091, 1025, 722; δH (400 MHz,
CDCl3) 6.68 (2H, t, J = 2.1), 6.22 (2H, t, J = 2.1), 4.64 (2H, s), 4.24
(2H, q, J = 7.1), 1.3 (3H, t, J = 7.1); δC (100 MHz, CDCl3) 168.7
(CO), 121.7 (2 × CH), 109.0 (2 × CH), 61.5 (CH2), 51.8 (CH2),
14.1 (CH3); MS (ESI) m/z 154.09 (MH+) and 176.07 (MNa+). Ethyl
1H-pyrrol-1-ylacetate (1.0 g, 6.528 mmol) was dissolved in THF/H2O
(20 mL) and cooled to 0 °C. NaOH (1.31 g, 32.6 mmol) was added
and the reaction mixture stirred at 0 °C for 30 min before being
washed with CH2Cl2 (20 mL). The aqueous phase was acidified with
concentrated HCl and extracted with CH2Cl2 (3 × 20 mL) before
being dried (MgSO4), filtered, and concentrated to give 1H-pyrrol-1-
ylacetic acid (8e; 775 mg, 95%), as brown solids: Rf 0.26 (ethyl
acetate); νmax (thin film)/cm−1 3074 (br), 2968, 2935, 1726, 1505,
1390, 1297, 1092, 727; δH (400 MHz, CDCl3) 9.31 (1H, br s), 6.67
(2H, t, J = 2.1), 6.24 (2H, t, J = 2.1), 4.71 (3H, s); δC (100 MHz,
CDCl3) 174.9 (CO), 121.8 (2 × CH), 109.3 (2 × CH), 50.3
(CH2); MS (ESI) m/z 126.06 (MH+) and 148.04 (MNa+).
a
AlCl3 (2.0 equiv) used instead of BF3·OEt2 and reaction run at 70 °C.
b
Toluene used in place of CHCl3, coupling time 20 min and
c
cyclization time 20 h. CH2Cl2 used in place of CHCl3, TFA used in
(E)-/(Z)-6-(Trimethylsilyl)hex-4-enoic Acid (8h). The title
compound was prepared using a modified procedure of Wardrop;50
4-pentenoic acid (500 mg, 510 μL, 4.99 mmol) and allyltrimethylsilane
(1.71 g, 2.38 mL, 1.50 mmol) were dissolved in CH2Cl2 (10 mL).
Hoveyda-Grubbs II catalyst (78.2 mg, 0.125 mmol) was added and the
resulting solution stirred at reflux for 5 h. The reaction mixture was
filtered through Celite and the filtrate concentrated to provide the
crude product. Purification by column chromatography (4/1
place of BF3·OEt2, and reaction run at 45 °C.
protected 3-hydroxypropanoic acid 2b,44 TBDMS-protected 4-
hydroxybutanoic acid 2c, TBDMS-protected 3-hydroxybutanoic acid
2d,45 2-(methoxycarbonyl)pentanedioic acid 1-methyl ester 8a,46 and
3-methyl-3-butenonic acid 8g.47
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petroleum ether/Et2O) gave the acid 8h (461 mg, 50%) as a clear,
colorless oil, as an approximately 2.8:1 mixture of isomers: Rf 0.2 (4/1
petroleum ether/Et2O); νmax (thin film)/cm−1 2954, 1709, 1412, 1247,
1153, 966, 837; δH (400 MHz, CDCl3) data for major isomer 5.53−
5.43 (1H, m), 5.30−5.20 (1H, m), 2.44−2.37 (2H, m), 2.37−2.27
(2H, m), 1.41 (2H, dd, J = 7.9 0.9), −0.02 (9H, s), data for minor
isomer 5.53−5.43 (1H, m), 5.30−5.20 (1H, m), 2.44−2.37 (2H, m),
2.37−2.27 (2H, m), 1.50 (2H, dd, J = 8.8, 1.2), 0.01 (9H, s); δC (100
MHz, CDCl3) data for major isomer 179.9 (CO), 128.1 (CH),
125.9 (CH), 34.6 (CH2), 27.9 (CH2), 22.7 (CH2), −2.1 (3 × CH3),
data for minor isomer 179.9 (CO), 127.4 (CH), 124.6 (CH), 34.2
(CH2), 22.3 (CH2), 18.5 (CH2), −1.8 (3 × CH3); HRMS (ESI) m/z
calcd 209.0968 for C9H18NaO2Si (MNa+), found 209.0962.
General Procedures for the DIA Reactions. General DIA
Procedure A (Table 1). To a solution of imine (1 mmol) and TBDMS-
protected carboxylic acid (1.2 mmol) in THF (10 mL) were added
sequentially NEt(i-Pr)2 (1.85 mmol) and then T3P (1.5 mmol, 50%
solution in THF). The resulting solution was stirred at room
temperature for 20 h, before it was poured into saturated aqueous
NaHCO3 (20 mL). The aqueous layer was extracted with ethyl acetate
(3 × 30 mL), washed with water (30 mL), and concentrated in vacuo.
The crude residue was then dissolved in CH2Cl2 (10 mL), SnCl2·
2H2O (5 mmol) was added, and the mixture was stirred at room
temperature for 20 h. The reaction was quenched by the addition of
excess solid K2CO3, and the mixture was then stirred for 5 min,
filtered, and concentrated in vacuo. Purification by column
chromatography (see individual entries for the solvents used for
chromatography) afforded the N,O-acetal product.
General DIA Procedure B (Table 2, Entries 1, 3, and 5). To a
solution of imine (1 mmol) and Cbz-protected amino acid (1.2 mmol)
in CHCl3 (10 mL) were added sequentially NEt(i-Pr)2 (1.85 mmol)
and then T3P (1.5 mmol, 50% solution in THF). The resulting
solution was stirred at 70 °C for 1 h, before it was cooled to room
temperature and poured into saturated aqueous NaHCO3 (20 mL).
The aqueous layer was extracted with CH2Cl2 (3 × 30 mL), washed
with water (30 mL), concentrated in vacuo, and passed through a
short silica column, with 1/1 petroleum ether/ethyl acetate as eluent.
The crude residue was then dissolved in methanol (10 mL) in a round-
bottomed flask that was purged with argon. Palladium hydroxide on
carbon (70 mg/mmol of imine, 20 wt %, 50% water) was then added
and the flask evacuated and back-filled with hydrogen several times.
The mixture was stirred under a small positive pressure of hydrogen
(balloon) for 1 h, before the hydrogen was evacuated and the reaction
flask back-filled with argon. The reaction mixture was then filtered
through Celite, rinsed with methanol, and concentrated in vacuo,
which afforded the product without the need for further purification.
General DIA Procedure C (Table 2, Entries 2 and 4). To a solution
of imine (1 mmol) and Boc-protected amino acid (1.2 mmol) in
CHCl3 (10 mL) were added sequentially NEt(i-Pr)2 (1.85 mmol) and
then T3P (1.5 mmol, 50% solution in THF). The resulting solution
was stirred at 70 °C for 1 h, before it was cooled to room temperature
and poured into saturated aqueous NaHCO3 (20 mL). The aqueous
layer was extracted with CH2Cl2 (3 × 30 mL), washed with water (30
mL), and concentrated in vacuo. The crude residue was then dissolved
in CH2Cl2 (5 mL) and cooled to 0 °C, and TFA (5 mL) was added.
The reaction mixture was warmed to room temperature and stirred for
15 min, before the solvent and TFA were removed in vacuo. The
residue was dissolved in CH2Cl2 (50 mL), and the solution was
washed with saturated aqueous NaHCO3 (25 mL), dried over MgSO4,
and concentrated in vacuo. Purification by column chromatography
(see individual entries for the solvents used for chromatography)
afforded the product.
vacuo. Purification by column chromatography (see individual entries
for the solvents used for chromatography) afforded the product.
General DIA Procedure E (Table 4). Imine 1d (100 mg, 0.762
mmol) and the appropriate carboxylic acid (0.915 mmol) were
dissolved in CHCl3 (4 mL) in a microwave vial and stirred at room
temperature. NEt(i-Pr)2 (182 mg, 246 μL, 1.410 mmol) and T3P (364
mg, 1.14 mmol, 728 mg of a 50% solution in THF) were added via
syringe. The reaction mixture was stirred at room temperature, 45 °C,
or 70 °C for 1 h. The appropriate acid or Lewis acid (1.525 mmol) was
added and the reaction mixture stirred at room temperature, 45 °C, or
70 °C for a further 1 h. The reaction was quenched with saturated
NaHCO3 (10 mL) and extracted with CH2Cl2 (3 × 10 mL). The
combined organic phases were dried (MgSO4), filtered, and
concentrated to give the crude material, which was purified by column
chromatography (see individual entries for the solvents used for
chromatography).
8,8-Dibenzyltetrahydro-2H-oxazolo[3,2-a]pyridin-3(5H)-one
(3a; Scheme 1). The compound was synthesized using general DIA
procedure A from imine 1a (24.9 mg, 0.0963 mmol) and acid 2b (22.0
mg, 0.116 mmol). Purification by column chromatography (4/1
petroleum ether/ethyl acetate) afforded the title compound 3a as a
colorless oil (21.0 mg, 68%): Rf 0.60 (ethyl acetate); νmax (thin film)/
cm−1 1713, 1445, 1287, 1084, 703; δH (400 MHz, CDCl3) 7.34−7.18
(8H, m), 7.08−7.04 (2H, m), 4.81 (1H, s), 4.37 (1H, d, J = 15.5) and
4.33 (1H, d, J = 15.5, AB system), 4.15−4.10 (1H, m), 2.96 (1H, d, J =
13.5), 2.92 (1H, d, J = 13.5), 2.72 (1H, d, J = 13.5), 2.60−2.51 (1H,
m), 2.38 (1H, d, J = 13.5), 2.04−1.92 (1H, m), 1.60−1.53 (2H, m),
1.28−1.18 (2H, m); δC (100 MHz, CDCl3) 168.2 (C), 137.1 (C),
136.4 (C), 131.1 (CH), 130.8 (CH), 128.2 (CH), 128.0 (CH), 126.4
(CH), 126.4 (CH), 91.7 (CH), 68.3 (CH2), 41.9 (C), 41.3 (CH2),
38.8 (CH2), 34.0 (CH2), 26.8 (CH2), 19.6 (CH2); HRMS (ESI+): m/z
calc. 344.1621 for C21H23NNaO2 (MNa+), found 344.1630.
9,9-Dibenzylhexahydropyrido[2,1-b][1,3]oxazin-4(6H)-one
(3b; Table 1, Entry 1). The compound was synthesized using general
DIA procedure A from imine 1a (53.0 mg, 0.201 mmol) and acid 2c
(49.2 mg, 0.241 mmol). Purification by column chromatography (4/1
→ 2/1 petroleum ether/ethyl acetate) afforded the title compound 3b
as a colorless oil (58.0 mg, 86%): Rf 0.65 (ethyl acetate); νmax (thin
film)/cm−1 2898, 1625, 1471, 1422, 1391, 1261, 1114, 1015, 720; δH
(400 MHz, CDCl3) 7.33−7.18 (8H, m), 7.10−7.06 (2H, m), 4.74−
4.67 (1H, m), 4.33 (1H, s), 4.25 (1H, dd, J = 11.0, 6.4), 3.76−3.69
(1H, m), 3.08 (1H, d, J = 13.1), 3.00 (1H, d, J = 13.5), 2.86 (1H, d, J =
13.5), 2.77−2.68 (1H, m), 2.38−2.20 (3H, m), 2.05−1.89 (1H, m),
1.54−1.46 (2H, m), 1.35−1.25 (1H, m); δC (100 MHz, CDCl3) 167.3
(C), 137.7 (C), 137.0 (C), 130.9 (CH), 130.9 (CH), 128.0 (CH),
127.9 (CH), 126.2 (CH), 126.2 (CH), 88.9 (CH), 62.3 (CH2), 41.7
(CH2), 41.4 (C), 40.1 (CH2), 35.2 (CH2), 33.1 (CH2), 27.8 (CH2),
20.2 (CH2); HRMS (ESI+) m/z calcd 336.1958 for C22H26NO2
(MH+), found 336.1953.
9,9-Dibenzyl-2-methylhexahydropyrido[2,1-b][1,3]oxazin-
4(6H)-one (3c; Table 1, Entry 2). The compound was synthesized
using general DIA procedure A from imine 1a (65.0 mg, 0.247 mmol)
and acid 2d (64.6 mg, 0.296 mmol). Purification by column
chromatography (2/1 → 1/1 petroleum ether/ethyl acetate) afforded
the title compound 3c as a colorless oil (71.0 mg, 82%) as a 2/1 (A/B)
mixture of diastereoisomers: Rf 0.55 (ethyl acetate); νmax (thin film)/
cm−1 2941, 1658, 1463, 1451, 1358, 1280, 1142, 703; δH (400 MHz,
CDCl3) 7.33−7.16 and 7.14−7.05 (20H, m, 10 from A and 10 from
B), 4.76−4.64 (2H, m, A and B), 4.36 (1H, s, A), 4.32 (1H, s, B),
3.85−3.77 (1H, m, B), 3.10 (1H, d, J = 13.2, B), 3.05−2.94 (3H, m, 2
from A and B), 2.89−2.77 (3H, m, 2 from A and B), 2.40−2.18 (7H,
m, 3 from A and 4 from B), 2.01−1.89 (2H, m, A and B), 1.55−1.45
(4H, m, A and B), 1.42 (3H, d, J = 6.2, B), 1.38−1.28 (2H, m, A and
B), 1.25 (3H, d, J = 6.6, A); δC (100 MHz, CDCl3) 167.6 (C, B), 166.4
(C, A), 137.9 (C, A and B), 137.2 (C, B), 137.0 (C, A), 131.1 (CH,
A), 131.0 (CH, B), 131.0 (CH, A), 130.9 (CH, B), 128.0 (CH, A),
128.0 (CH, B), 127.9 (CH, B), 127.8 (CH, A), 126.3 (CH, A), 126.2
(CH, B), 126.2 (CH, A and B), 88.6 (CH, B), 83.4 (CH, A), 68.8
(CH, B), 67.1 (CH, A), 41.7 (C, A), 41.6 (C, B), 41.5 (CH2, B), 41.3
(CH2, A), 40.2 (CH2, B), 40.1 (CH2, B), 39.8 (CH2, A), 37.9 (CH2,
General DIA Procedure D (Table 3). To a solution of imine (1
mmol) and thiol-carboxylic acid (1.2 mmol) in CHCl3 (10 mL) were
added sequentially NEt(i-Pr)2 (1.85 mmol) and then T3P (1.5 mmol,
50% solution in THF). The resulting solution was stirred at room
temperature for 1 h, before it was poured into 10% aqueous K2CO3
(20 mL). The aqueous layer was extracted with CH2Cl2 (3 × 30 mL),
and the extract was washed with water (30 mL) and concentrated in
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A), 35.3 (CH2, B), 35.2 (CH2, A), 28.0 (CH2, A), 27.9 (CH2, B), 21.1
(CH2, B), 20.4 (CH2, A), 20.2 (CH2, B), 17.2 (CH2, A); HRMS
(ESI+) m/z calcd 350.2115 for C23H28NO2 (MH+), found 350.2104.
2-Methylhexahydropyrido[2,1-b][1,3]oxazin-4(6H)-one (3d;
Table 1, Entry 3). The compound was synthesized using general
DIA procedure A from dodecahydro-4a,8a,12a-triazatriphenylene (the
trimer of imine 1b; 50.0 mg, 0.201 mmol) and acid 2d (131 mg, 0.603
mmol). Purification by column chromatography (2/1 → 1/1
petroleum ether/ethyl acetate → ethyl acetate) afforded the title
compound 3d as a pale yellow oil (61.0 mg, 60%) as an 8/1 (A/B)
mixture of diastereoisomers: Rf 0.20 (ethyl acetate); δH (400 MHz,
CDCl3) 4.77−4.70 (1H, m, B), 4.70−4.66 (2H, m, A and B), 4.62−
4.57 (1H, m, A), 4.26−4.18 (1H, m, B), 3.91−3.82 (1H, m, A), 2.55−
2.18 (6H, m, 3 from A and 3 from B), 2.04−1.64 (6H, m, 3 from A
and 3 from B), 1.55−1.30 (6H, m, 3 from A and 3 from B), 1.27 (6H,
d, J = 6.2, 3 from A and 3 from B); δC (100 MHz, CDCl3) 166.8 (C, A
and B), 88.2 (CH, A), 83.9 (CH, B), 69.5 (CH, A), 65.8 (CH, B), 41.1
(CH2, B), 40.1 (CH2, A), 39.8 (CH2, A), 39.1 (CH2, B), 32.8 (CH2,
A), 32.0 (CH2, B), 24.8 (CH2, B), 24.5 (CH2, A), 23.4 (CH2, B), 22.6
(CH2, A), 21.0 (CH3, A), 19.8 (CH3, B). Spectral data are in accord
with those reported in the literature.11
8,8-Dibenzyl-2-methyltetrahydro-2H-pyrrolo[2,1-b][1,3]-
oxazin-4(3H)-one (3e; Table 1, Entry 4). The compound was
synthesized using general DIA procedure A from imine 1c (50.0 mg,
0.201 mmol) and acid 2d (48.2 mg, 0.221 mmol). Purification by
column chromatography (2/1 → 1/1 petroleum ether/ethyl acetate)
afforded the title compound 3e as a colorless oil (42.0 mg, 62%) as a
6/1 (A/B) mixture of diastereoisomers: Rf 0.40 (ethyl acetate); νmax
(thin film)/cm−1 2930, 1644, 1455, 1391, 1126, 757, 703; δH (400
MHz, CDCl3) 7.34−7.16 (16H, m, 8 from A and 8 from B), 7.08−
7.03 (4H, m, 2 from A and 2 from B), 4.74 (1H, s, B), 4.64 (1H, s, A),
4.52−4.47 (1H, m, B), 3.95−3.87 (1H, m, A), 3.60−3.43 (2H, m, A
and B), 3.30−3.19 (2H, m, A and B), 2.91 (1H, d, J = 13.7, A), 2.86
(1H, d, J = 13.7, B), 2.79−2.61 (7H, m, 3 from A and 4 from B), 2.39
(1H, dd, J = 17.6, 4.0, A), 2.26−2.09 (2H, m, A and B), 1.77−1.67
(2H, m, A and B), 1.57−1.45 (2H, m, A and B), 1.42 (3H, d, J = 6.0,
A), 1.34 (3H, d, J = 6.6, B); δC (100 MHz, CDCl3) 166.7 (C, A and
B), 137.6 (C, B), 137.5 (C, A), 136.7 (C, A), 136.6 (C, B), 130.9 (CH,
B), 130.8 (CH, A), 128.2 (CH, A and B), 128.1 (CH, A and B), 126.6
(CH, B), 126.5 (CH, A), 126.5 (CH, A and B), 90.4 (CH, A), 84.0
(CH, B), 72.0 (CH, A), 69.1 (CH, B), 47.4 (C, B), 47.1 (C, A), 40.7
(CH2, B), 40.4 (CH2, A and B), 39.9 (CH2, A), 38.6 (CH2, A), 37.3
(CH2, A and B), 37.0 (CH2, B), 24.9 (CH2, B), 24.7 (CH2, A), 21.4
(CH3, A), 19.7 (CH3, B); HRMS (ESI+) m/z calcd 336.1958 for
C22H26NO2 (MH+), found 336.1958.
2-Methyl-2,3,6,7-tetrahydro[1,3]oxazino[2,3-a]isoquinolin-
4(11bH)-one (3f; Table 1, Entry 5). To a solution of imine 1d (210
mg, 1.60 mmol) and TBDMS-protected carboxylic acid 2d (419 mg,
1.92 mmol) in CH2Cl2 (11.1 mL) were added sequentially NEt(i-Pr)2
(0.520 mL, 2.96 mmol) and then T3P (1.53 g, 2.40 mmol, 50%
solution in THF). The resulting solution was stirred at room
temperature for 20 h. SnCl2·2H2O (2.49 mmol, 11.2 mmol) was
then added directly to the reaction mixture, which was stirred at room
temperature for a further 24 h. The reaction was quenched by the
addition of 10% aqueous K2CO3, and the mixture was diluted with
water (50 mL), extracted with CH2Cl2 (3 × 50 mL), washed with
water (50 mL), dried over MgSO4, and concentrated in vacuo.
Purification by column chromatography (1/1 petroleum ether/ethyl
acetate) afforded the title compound 3f as a colorless oil (254 mg,
73%) as a 20/1 (A/B) mixture of diastereoisomers: Rf 0.40 (ethyl
acetate); νmax (thin film)/cm−1 2800, 1650, 1463, 1391, 1374, 1307,
1166, 1123, 747; δH (400 MHz, CDCl3; data for the major
diastereoisomer A only) 7.51−7.47 (1H, m), 7.28−7.22 (2H, m),
7.14−7.09 (1H, m), 5.86 (1H, s), 4.67−4.60 (1H, m), 4.20−4.10 (1H,
m), 3.09−2.92 (1H, m), 2.73−2.67 (1H, m), 2.52 (1H, dd, J = 17.2,
3.7), 2.37 (1H, dd, J = 17.2, 11.4), 1.37 (3H, d, J = 6.2); δC (100 MHz,
CDCl3) 166.2 (C), 134.8 (C), 133.5 (C), 128.3 (CH), 128.2 (CH),
126.6 (CH), 126.0 (CH), 84.1 (CH), 70.3 (CH), 39.3 (CH2), 37.4
(CH2), 27.8 (CH2), 21.1 (CH3); HRMS (ESI+) m/z calcd 240.0995
for C13H15NNaO2 (MNa+), found 240.0991.
Characteristic NMR data for the minor diastereoisomer B: δH (400
MHz, CDCl3) 5.98 (1H, s); δC (100 MHz, CDCl3) 82.3 (CH).
3,6-Dimethyl-2-phenyl-1,3-oxazinan-4-one (3g; Table 1,
Entry 6). To a solution of imine 1e (98.0 μL, 0.795 mmol) and
TBDMS-protected carboxylic acid 2d (208 mg, 0.954 mmol) in
chloroform (5.5 mL) were added sequentially DIPEA (0.260 mL, 1.47
mmol) and then T3P (1759 mg, 1.19 mmol, 50% solution in THF).
The resulting solution was heated to reflux for 1 h and then cooled to
0 °C. Triflic acid (0.700 mL, 7.95 mmol) was then added directly to
the reaction mixture, which was warmed to room temperature and
stirred for a further 1 h. The reaction was quenched by the addition of
1 M aqueous NaOH (25 mL), extracted with CH2Cl2 (3 × 50 mL),
washed with water (50 mL), dried over MgSO4, and concentrated in
vacuo. Purification by column chromatography (1/1 petroleum ether/
ethyl acetate) afforded the title compound 3g as a colorless oil (106
mg, 65%) as a 12/1 (A/B) mixture of diastereoisomers: Rf 0.25 (ethyl
acetate); νmax (thin film)/cm−1 3432, 1643, 1456, 1389, 1350, 1301,
1152, 755, 701; δH (400 MHz, CDCl3) 7.42−7.35 (10H, m, 5 from A
and 5 from B), 5.81 (1H, s, B), 5.58 (1H, s, A), 4.14−4.05 (1H, m, A),
3.93−3.85 (1H, m, B), 2.87 (3H, s, B), 2.58 (3H, s, A), 2.55−2.51
(4H, m, 2 from A and 2 from B), 1.32 (3H, d, J = 6.1, A), 1.15 (3H, d,
J = 6.1, B); δC (100 MHz, CDCl3; data for the major diastereoisomer
A only) 167.9 (C), 137.5 (C), 129.8 (CH), 128.9 (CH), 127.5 (CH),
90.9 (CH), 70.7 (CH), 40.0 (CH2), 29.8 (CH3), 21.1 (CH3); HRMS
(ESI+) m/z calcd 206.1176 for C12H16NO2 (MH+), found 206.1176.
8,8-Dibenzylhexahydroimidazo[1,2-a]pyridin-3(5H)-one (5a;
Table 2, Entry 1). Synthesis using general DIA procedure B from
imine 1a (27.0 mg, 0.103 mmol) and protected amino acid 4a (25.9
mg, 0.124 mmol) afforded the title compound 5a as a colorless oil
(28.5 mg, 86%): Rf 0.25 (ethyl acetate); νmax (thin film)/cm−1 3344
(br), 2940, 1680, 1452, 1293, 910; δH (400 MHz, CDCl3) 7.34−7.10
(8H, m), 7.08−6.98 (2H, m), 4.30 (1H, s), 4.15 (1H, dd, J = 12.8,
4.8), 3.69 (1H, d, J = 15.8), 3.55 (1H, d, J = 15.8), 2.99 (1H, d, J =
13.5), 2.86 (1H, d, J = 13.0), 2.79 (1H, d, J = 13.0), 2.57−2.48 (1H,
m), 2.37 (1H, d, J = 13.5), 2.05−1.90 (1H, m), 1.63−1.50 (2H, m),
1.35−1.20 (1H, m); δC (100 MHz, CDCl3) 182.5 (C), 137.4 (C),
137.1 (C), 131.0 (CH), 130.9 (CH), 128.3 (CH), 128.3 (CH), 126.6
(CH), 126.5 (CH), 76.7 (CH), 49.3 (CH2), 43.0 (C), 41.8 (CH2),
39.5 (CH2), 34.1 (CH2), 27.9 (CH2), 20.1 (CH2); HRMS (ESI+) m/z
calcd 321.1961 for C21H25N2O (MH+), found 321.1955.
9,9-Dibenzylhexahydro-1H-pyrido[1,2-a]pyrimidin-4(6H)-
one (5b; Table 2, Entry 2). The compound was synthesized using
general DIA procedure C from imine 1a (53.0 mg, 0.201 mmol) and
acid 4b (49.2 mg, 0.241 mmol). Purification by column chromatog-
raphy (1/1 petroleum ether/ethyl acetate → ethyl acetate) afforded
the title compound 5b as a pale yellow solid (82.0 mg, 76%): Rf 0.65
(ethyl acetate); mp 102−104 °C; νmax (thin film)/cm−1 3344 (br),
2943, 1632, 1454, 1360, 1280, 910; δH (400 MHz, CDCl3) 7.34−7.17
(10H, m), 4.78−4.72 (1H, m), 3.92 (1H, s), 3.30−3.24 (1H, m), 3.17
(1H, d, J = 13.1), 3.01 (1H, d, J = 13.1), 2.86−2.79 (1H, m), 2.62 (1H,
d, J = 13.1), 2.44−2.36 (3H, m), 2.27−2.17 (1H, m), 1.98−1.85 (1H,
m), 1.53−1.40 (2H, m), 1.36−1.25 (1H, m); δC (100 MHz, CDCl3)
169.8 (C), 137.2 (C), 137.1 (C), 131.0 (CH), 130.9 (CH), 128.2
(CH), 127.8 (CH), 126.5 (CH), 126.3 (CH), 75.2 (CH), 42.0 (CH2),
41.2 (C), 40.8 (CH2), 40.1 (CH2), 36.4 (CH2), 34.6 (CH2), 29.6
(CH2), 20.4 (CH2); HRMS (ESI+) m/z calcd 335.2118 for
C22H27N2O (MH+), found 335.2107.
(2S)-2-Methyl-1,2,5,6-tetrahydroimidazo[2,1-a]isoquinolin-
3(10bH)-one (5c; Table 2, Entry 3). Synthesis using general DIA
procedure B from imine 1d (57.0 mg, 0.434 mmol) and protected
amino acid 4c (116 mg, 0.521 mmol) afforded the title compound 5c
as a colorless oil (79 mg, 90%) as a 4/1 (A/B) mixture of
diastereoisomers: Rf 0.10 (ethyl acetate); νmax (thin film)/cm−1 3406
(br), 1682, 1439, 1354, 1306, 737; δH (400 MHz, CDCl3) 7.51−7.14
(8H, m, 4 from A and 4 from B), 5.70 (1H, s, B), 5.57 (1H, s, A),
4.20−4.13 (2H, m, A and B), 3.75−3.64 (2H, m, A and B), 3.27−3.14
(2H, m, A and B), 3.03−2.92 (2H, m, A and B), 2.84−2.73 (2H, m, A
and B), 1.44 (3H, d, J = 6.8, B), 1.37 (3H, d, J = 6.8, A); δC (100 MHz,
CDCl3) 173.4 (C, A and B), 134.2 (C, B), 134.0 (C, A), 133.8 (C, A
and B), 129.2 (CH, A), 129.1 (CH, B), 128.6 (CH, B), 128.4 (CH, A),
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127.2 (CH, A), 127.1 (CH, B), 125.4 (CH, A), 125.4 (CH, B), 69.7
(CH, B), 69.6 (CH, A), 56.4 (CH, A), 55.9 (CH, B), 37.2 (CH2, B),
36.8 (CH2, A), 28.3 (CH2, A), 27.9 (CH2, B), 16.4 (CH3, B), 15.9
(CH2, A); HRMS (ESI+) m/z calcd 203.1179 for C12H15N2O (MH+),
found 203.1174.
(CH, B), 126.6 (CH, A), 126.5 (CH, B), 65.0 (CH, B), 63.5 (CH, A),
53.3 (CH, B), 52.3 (CH, A), 46.5 (CH2, A), 46.2 (C, A), 45.5 (CH2,
B), 43.3 (C, B), 42.1 (CH2, A), 41.1 (CH2, B), 37.0 (CH2, A), 36.2
(CH2, B), 29.7 (CH2, A), 29.6 (CH2, B), 28.1 (CH2, A), 26.9 (CH2,
B), 23.3 (CH3, A), 23.2 (CH3, B), 21.2 (CH2, A), 21.0 (CH2, B);
HRMS (ESI+) m/z calcd 409.1944 for C24H29N2O2S (MH+), found
409.1945.
(8aS)-5,6,8a,9,10,11-Hexahydropyrrolo[1′,2’:3,4]imidazo-
[2,1-a]isoquinolin-8(12aH)-one (5d; Table 2, Entry 4). The
compound was synthesized using general DIA procedure C from imine
1d (57.0 mg, 0.434 mmol) and acid 4d (106 mg, 0.521 mmol).
Purification by column chromatography (100/1 → 50/1 ethyl acetate/
methanol) afforded the title compound 5d as a colorless oil (74.0 mg,
75%): Rf 0.10 (100/1 ethyl acetate/methanol); νmax (thin film)/cm−1
3442, 2967, 1694, 1650, 1433, 1368, 1303, 1199, 1057, 748; δH (400
MHz, CDCl3) 7.44 (1H, d, J = 7.5), 7.31−7.23 (2H, m), 7.14 (1H, d, J
= 7.3), 5.82 (1H, s), 4.25 (1H, ddd, J = 13.2, 5.7, 1.5), 3.94 (1H, dd, J
= 8.6, 4.6), 3.11−3.02 (1H, m), 2.92−2.74 (2H, m), 2.59−2.53 (1H,
m), 2.23−2.07 (2H, m), 1.95−1.87 (1H, m), 1.76−1.67 (2H, m); δC
(100 MHz, CDCl3) 174.6 (C), 134.8 (C), 131.7 (C), 129.2 (CH),
127.9 (CH), 127.3 (CH), 127.0 (CH), 73.4 (CH), 66.4 (CH), 48.1
(CH2), 36.9 (CH2), 29.0 (CH2), 25.4 (CH2), 24.3 (CH2); HRMS
(ESI+) m/z calcd 229.1335 for C14H17N2O (MH+), found 229.1335;
11b-Methyl-2,3,6,7-tetrahydro[1,3]thiazino[2,3-a]-
isoquinolin-4(11bH)-one (7c; Table 3, Entry 3). The compound
was synthesized using general DIA procedure D from imine 1g (57.0
mg, 0.393 mmol) and thioacid 6a (41.0 μL, 0.471 mmol). Purification
by column chromatography (1/1 → 1/2 petroleum ether/ethyl
acetate) afforded the title compound 7c as a colorless oil (82 mg,
89%): Rf 0.10 (ethyl acetate); νmax (thin film)/cm−1 1607, 1372, 1330,
1067, 751; δH (400 MHz, CDCl3) 7.43 (1H, d, J = 7.5), 7.26−7.17
(2H, m), 7.12 (1H, d, J = 7.3), 5.10 (1H, ddd, J = 13.0, 4.9, 1.7), 3.24
(1H, ddd, J = 15.6, 9.9, 5.1), 3.03−2.93 (1H, m), 2.87−2.67 (4H, m),
2.04 (3H, s); δC (100 MHz, CDCl3) 168.0 (C), 139.1 (C), 134.1 (C),
129.1 (CH), 127.4 (CH), 126.7 (CH), 126.1 (CH), 65.3 (C), 36.7
(CH2), 33.8 (CH2), 30.5 (CH3), 29.1 (CH2), 22.5 (CH2); HRMS
(ESI+) m/z calcd 234.0947 for C13H16NOS (MH+), found 234.0948.
10b-Phenyl-5,6-dihydro-2H-thiazolo[2,3-a]isoquinolin-3-
(10bH)-one (7d; Table 3, Entry 4). The compound was synthesized
using general DIA procedure D from imine 1h (58.0 mg, 0.280 mmol)
and thioacid 6c (23.3 μL, 0.336 mmol). Purification by column
chromatography (3/1 petroleum ether/ethyl acetate) afforded the title
compound 7d as a colorless oil (73 mg, 93%): Rf 0.30 (ethyl acetate);
νmax (thin film)/cm−1 1653, 1380, 1271, 1157, 739; δH (400 MHz,
CDCl3) 7.50−7.46 (1H, m), 7.33−7.13 (8H, m), 4.12 (1H, ddd, J =
13.0, 7.0, 4.6), 3.98 (1H, d, J = 15.5), 3.73 (1H, d, J = 15.5), 3.17 (1H,
ddd, J = 13.0, 9.0, 6.0), 3.06−3.00 (1H, m), 2.64 (1H, ddd, J = 16.3,
6.0, 4.6); δC (100 MHz, CDCl3) 169.8 (C), 144.0 (C), 138.8 (C),
133.4 (C), 128.8 (CH), 128.4 (CH), 128.2 (CH), 128.1 (CH), 127.6
(CH), 126.8 (CH), 126.4 (CH), 73.4 (C), 38.1 (CH2), 34.3 (CH2),
27.1 (CH3); HRMS (ESI+) m/z calcd 282.0947 for C17H16NOS
(MH+), found 282.0954.
22
[α]D −21.0° (c 0.9, CHCl3).
5,6,11,11b-Tetrahydro-1H-imidazo[1′,2’:1,2]pyrido[3,4-b]-
indol-3(2H)-one (5e; Table 2, Entry 5). The compound was
synthesized using general DIA procedure B from imine 1f (35.0 mg,
0.206 mmol) and protected amino acid 4a (51.7 mg, 0.247 mmol),
affording the title compound 5e as a colorless oil (40 mg, 85%): Rf
0.10 (100/1 ethyl acetate/methanol); νmax (thin film)/cm−1 3141 (br),
1643, 1424, 1285, 734; δH (400 MHz, d6-DMSO) 11.09 (1H, br s),
7.39 (1H, d, J = 7.9), 7.31 (1H, d, J = 7.9), 7.05 (1H, dd, J = 7.9, 6.7),
6.95 (1H, dd, J = 7.9, 6.7), 5.71 (1H, s), 4.19−4.13 (1H, m), 3.42 (1H,
d, J = 15.8), 3.20−3.08 (2H, m), 2.73−2.65 (1H, m); δC (100 MHz,
d6-DMSO) 173.1 (C), 136.3 (C), 132.8 (C), 126.2 (C), 121.5 (CH),
118.6 (CH), 118.2 (CH), 111.5 (CH), 107.7 (C), 69.6 (CH), 49.6
(CH2), 37.4 (CH2), 20.4 (CH2); HRMS (ESI+) m/z calcd 228.1131
for C13H14N3O (MH+), found 228.1134.
9,9-Dibenzylhexahydropyrido[2,1-b][1,3]thiazin-4(6H)-one
(7a; Table 3, Entry 1). The compound was synthesized using general
DIA procedure D from imine 1a (25.0 mg, 0.0950 mmol) and thioacid
6a (9.9 μL, 0.247 mmol). Purification by column chromatography (1/
1 petroleum ether/ethyl acetate) afforded the title compound 7a as a
colorless oil (30 mg, 90%): Rf 0.60 (ethyl acetate); νmax (thin film)/
cm−1 2941, 1642, 1454, 1360, 1327, 1185, 912; δH (400 MHz, CDCl3)
7.34−7.16 (10H, m), 5.00−4.94 (1H, m), 4.40 (1H, s), 3.10−2.91
(4H, m), 2.88−2.74 (3H, m), 2.40 (1H, d, J = 14.0), 2.28−2.18 (1H,
m), 2.06−1.94 (1H, m), 1.62−1.49 (2H, m), 1.40−1.30 (1H, m); δC
(100 MHz, CDCl3) 169.6 (C), 137.4 (C), 136.4 (C), 131.0 (CH),
130.9 (CH), 128.1 (CH), 128.0 (CH), 126.5 (CH), 126.4 (CH), 64.9
(CH), 44.8 (CH2), 44.3 (C), 42.0 (CH2), 36.6 (CH2), 35.5 (CH2),
29.9 (CH2), 23.0 (CH2), 20.1 (CH2); HRMS (ESI+) m/z calcd
352.1730 for C22H26NOS (MH+), found 352.1728.
5,6,11,11b-Tetrahydrothiazolo[3′,2’:1,2]pyrido[3,4-b]indol-
3(2H)-one (7e; Table 3, Entry 5). The compound was synthesized
using general DIA procedure D from imine 1f (35.0 mg, 0.206 mmol)
and thioacid 6c (17.2 μL, 0.247 mmol). Purification by column
chromatography (1/1 petroleum ether/ethyl acetate) afforded the title
compound 7e as a colorless oil (49 mg, 97%): Rf 0.35 (ethyl acetate);
νmax (thin film)/cm−1 3168, 1624, 1420, 1302, 1214, 885; δH (400
MHz, d6-DMSO) 11.51 (1H, br s), 7.40 (1H, d, J = 7.7), 7.29 (1H, d, J
= 8.1), 7.07−7.03 (1H, m), 6.98−6.94 (1H, m), 6.22 (1H, s), 4.34
(1H, dd, J = 13.2, 4.4), 3.81 (1H, d, J = 15.2), 3.57 (1H, d, J = 15.2),
3.19−3.11 (1H, m), 2.78−2.62 (2H, m); δC (100 MHz, d6-DMSO)
170.1 (C), 137.0 (C), 132.6 (C), 126.5 (C), 122.3 (CH), 119.5 (CH),
118.9 (CH), 112.0 (CH), 107.8 (C), 56.1 (CH), 40.9 (CH2), 33.5
(CH2), 21.2 (CH3); HRMS (ESI+) m/z calcd 245.0743 for
C13H13N2OS (MH+), found 245.0753.
N-((3R)-9,9-Dibenzyl-4-oxooctahydropyrido[2,1-b][1,3]-
thiazin-3-yl)acetamide (7b; Table 3, Entry 2). The compound was
synthesized using general DIA procedure D from imine 1a (34 mg,
0.129 mmol) and thioacid 6b (25.3 mg, 0.155 mmol). Purification by
column chromatography (1/1 petroleum ether/ethyl acetate) afforded
the title compound 7b as a colorless oil (47 mg, 89%) as a 4/1 (A/B)
mixture of diastereoisomers: Rf 0.2 (ethyl acetate); νmax (thin film)/
cm−1 3260, 2894, 1608, 1419, 720; δH (400 MHz, CDCl3) 7.35−7.15
(18H, m, 8 from A and 10 from B), 7.05 (2H, d, J = 6.6, A), 6.94−6.91
(1H, m, B, NH), 6.78−6.75 (1H, m, A, NH), 4.89−4.82 (2H, m, A
and B), 4.64−4.52 (2H, m, A and B), 4.49 (1H, s, B), 4.16 (1H, s, A),
3.49−3.40 (2H, m, A and B), 3.24−3.18 (2H, m, A and B), 3.05−2.97
(3H, m, A), 2.96−2.82 (2H, m, B), 2.67−2.60 (1H, m, B), 2.42−2.30
(4H, m, 2 from A and 2 from B), 2.02 (3H, s, B), 2.01 (3H, s, A),
2.00−1.90 (2H, m, A and B), 1.64−1.52 (4H, m, 2 from A and 2 from
B), 1.45−1.35 (1H, m, A), 1.35−1.25 (1H, m, B); δC (100 MHz,
CDCl3) 170.6 (C, A), 170.4 (C, B), 169.0 (C, B), 168.2 (C, A), 137.2
(C, B), 136.7 (C, A), 136.3 (C, A), 135.9 (C, B), 131.0 (CH, A and
B), 130.9 (CH, A and B), 128.2 (CH, 2 from A and 1 from B), 128.0
3-Methyl-2-phenylthiazolidin-4-one (7f; Table 3, Entry 6).
The compound was synthesized using general DIA procedure D from
imine 1e (90.8 mg, 0.726 mmol) and thioacid 6c (84.3 mg, 63.8 μL,
0.915 mmol). Purification by column chromatography (1/1 petroleum
ether/ethyl acetate) afforded the title compound 7f as a colorless oil
(173 mg, 93%): Rf 0.35 (ethyl acetate); νmax (thin film)/cm−1 3031,
2922, 1670, 1389, 697; δH (400 MHz, CDCl3) 7.44−7.34 (3H, m),
7.33−7.28 (2H, m), 5.52 (1H, d, J = 2.1), 3.84 (1H, dd, J = 15.4, 2.1),
3.72 (1H, d, J = 15.4), 2.74 (3H, s); δC (100 MHz, CHCl3) 171.13
(CO), 139.12 (C), 129.1 (2 × CH), 129.0 (2 × CH), 126.8 (CH),
65.3 (CH), 32.9 (CH2), 30.1 (CH3); HRMS (ESI+) m/z calcd
194.0634 for C10H12NOS (MH+), found 194.0630. These data were
consistent with those reported in the literature.12
Dimethyl 4-Oxo-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]-
isoquinoline-1,1(2H,11bH)-dicarboxylate (9a, Table 4, entry
1). Imine 1d (50 mg, 0.381 mmol) and carboxylic acid 8a (93 mg,
0.457 mmol) were dissolved in CHCl3 (2 mL) in a microwave vial.
NEt(i-Pr)2 (91.1 mg, 123 μL, 0.705 mmol) and T3P (182 mg, 0.572
mmol, 364 mg of a 50% solution in THF) were added via syringe. The
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reaction mixture was stirred at 70 °C for 1 h. AlCl3 (102 mg, 0.762
mmol) was added and the reaction mixture stirred at 70 °C for 1 h.
The reaction mixture was quenched with saturated NaHCO3 (5 mL)
and extracted with CH2Cl2 (3 × 5 mL). The combined organic phases
were dried (MgSO4), filtered, and concentrated to give the crude
material. Purification by column chromatography (ethyl acetate) gave
the title compound 9a (92 mg, 76%) as a yellow solid: mp 130−133
°C (from CHCl3); Rf 0.48 (ethyl acetate); νmax (thin film)/cm−1 2952,
2874, 1741, 1713, 1668, 1399, 1276, 1159, 1078, 759; δH (400 MHz,
CDCl3) 7.27−7.12 (4H, m), 5.49 (1H, m), 4.67−4.55 (1H, m), 3.82
(3H, s), 3.36 (3H, s), 2.94−2.83 (2H, m), 2.77−2.65 (1H, m), 2.66−
2.43 (4 H, m); δC (100 MHz, CDCl3) 171.2 (CO), 170.9 (CO),
169.1 (CO), 137.5 (C), 132.9 (C), 128.3 (CH), 127.4 (CH), 126.5
(CH), 126.1 (CH), 60.1 (C), 59.0 (CH), 53.1 (CH3), 52.5 (CH3),
39.7 (CH2), 29.5 (CH2), 28.7 (CH2), 28.7 (CH2); HRMS (ESI) m/z
calcd 318.1336 for C17H20NO5 (MH+), found 318.1335.
1,1′-(4-Oxo-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]-
isoquinoline-1,1-diyl)diethanone (9b; Table 4, Entry 2). The
compound was synthesized using general DIA procedure E (at 70 °C
and with AlCl3 as the Lewis acid) from imine 1d (100 mg, 0.762
mmol) and carboxylic acid 8b (158 mg, 0.915 mmol). Purification by
column chromatography (ethyl acetate) gave the title compound 9b
(141 mg, 65%) as a colorless solid: mp 146−147 °C (from petroleum
ether/EtOAc); Rf 0.25 (ethyl acetate); νmax (thin film)/cm−1 3014,
2947, 2921, 1687, 1660, 1464, 1402, 1356, 1186, 1136, 759; δH (400
MHz, CDCl3) 7.26−7.20 (1H, m), 7.20−7.14 (2H, m), 7.09−7.04
(1H, m), 5.67 (1H, s), 4.36 (1H, dt, J = 12.7, 5.8), 3.18−3.09 (1H, m),
2.87 (2H, app t, J = 6.6), 2.59−2.40 (3H, m), 2.38−2.29 (1H, m), 2.28
(3H, s), 1.82 (3H, s); δC (100 MHz, CDCl3) 204.2 (CO), 203.8
(CO), 170.3 (CO), 137.2 (C), 133.8 (C), 129.0 (CH), 127.9
(CH), 126.6 (CH), 125.5 (CH), 71.2 (C), 56.2 (CH), 40.3 (CH2),
29.1 (CH2), 28.2 (CH3), 28.0 (CH2), 26.8 (CH3), 24.2 (CH2); HRMS
(ESI) m/z calcd 286.1438 for C17H20NO3 (MH+), found 286.1430.
2,3-Dimethoxy-8,9-dihydro-5H-isoquinolino[1,2-a]-
isoquinolin-6(13bH)-one (9c; Table 4, Entry 3). The compound
was synthesized using general DIA procedure E (at room temperature
and with BF3·OEt2 as the Lewis acid) from imine 1d (100 mg, 0.762
mmol) and carboxylic acid 8c (179 mg, 0.915 mmol). Purification by
column chromatography (ethyl acetate) gave the title compound 9c
(212 mg, 90%) as a yellow solid: mp 175−177 °C (from EtOAc/
MeOH) (lit.13 mp 141−142 °C (from EtOH/petroleum ether)); Rf
0.30 (ethyl acetate); νmax (thin film)/cm−1 2932, 1629, 1520, 1461,
1251, 758, 601; δH (400 MHz, CDCl3) 7.31−7.28 (3H, m), 7.03 (1H,
d, J = 7.3), 6.73 (1H, s), 6.57 (1H, s), 5.64 (1H, s), 4.61 (1H, ddd, J =
13.0, 6.2, 5.2), 3.91 (3H, s), 3.80 (3H, s), 3.60 (1H, d, J = 18.9), 3.51
(1H, d, J = 18.9), 3.29 (1H, ddd, J = 13.0, 8.8, 5.2), 3.03 (1H, ddd, J =
15.4, 8.8, 6.2), 2.91 (1H, app dt, J = 15.9, 5.2); δC (100 MHz, CDCl3)
169.5 (CO), 148.7 (C), 147.4 (C), 136.0 (C), 135.7 (C), 128.8
(CH), 127.6 (CH), 126.1 (CH), 125.8 (CH), 125.3 (C), 125.2 (C),
110.3 (CH), 109.7 (CH), 59.0 (CH), 56.0 (CH3), 56.0 (CH3), 40.9
(CH2), 37.3 (CH2), 28.1 (CH2); HRMS (ESI) m/z calcd 310.1438 for
C19H20NO3 (MH+), found 310.1437.
8,9-Dihydro-5H-pyrrolo[2′,1’:3,4]pyrazino[2,1-a]isoquinolin-
6(13bH)-one (9e; Table 4, Entry 5). The compound was
synthesized using general DIA procedure E (at room temperature
and with BF3·OEt2 as the Lewis acid) from imine 1d (100 mg, 0.762
mmol) and carboxylic acid 8e (115 mg, 0.915 mmol). Purification by
column chromatography (1/1 petroleum ether/ethyl acetate) gave the
title compound 9e (140 mg, 77%) as a brown oil: Rf 0.65 (ethyl
acetate); νmax (thin film)/cm−1 2944, 2897, 1651, 1448, 1427, 1317,
908, 724; δH (400 MHz, CDCl3); 7.41−7.35 (1H, m), 7.31−7.24 (2H,
m), 7.24−7.19 (1H, m), 6.70 (1H, dd, J = 2.6, 1.6), 6.23 (1H, dd, J =
3.6, 2.6), 5.99 (1H, ddd, J = 3.6, 1.6, 1.0), 5.90 (1H, s), 4.76 (1H, ddd,
J = 12.6, 5.4, 3.6), 4.69 (1H, d, J = 17.1), 4.62 (1H, d, J = 17.1), 3.22−
3.13 (1H, m), 3.12−3.01 (1H, m), 2.86 (1H, app dt, J = 15.8, 3.6); δC
(100 MHz, CDCl3) 165.3 (CO), 134.8 (C), 133.5 (C), 129.0
(CH), 127.6 (CH), 126.3 (CH), 125.5 (CH), 119.2 (CH), 108.9
(CH), 105.7 (CH), 54.2 (CH), 48.9 (CH2), 40.4 (CH2), 28.2 (CH2);
HRMS (ESI) m/z calcd 239.1179 for C15H15N2O (MH+), found
239.1179.
11,14-Dimethoxy-5,6-dihydrobenzo[de]isoquinolino[1,2-a]-
isoquinolin-8(14bH)-one (9f; Table 4, Entry 6). Imine 1d (53.4
mg, 0.407 mmol) and carboxylic acid 8f (113 mg, 0.489 mmol) were
dissolved in toluene (2.5 mL). NEt(i-Pr)2 (97.3 mg, 131 μL, 0.753
mmol) and T3P (194 mg, 0.611 mmol, 386 mg of a 50% solution in
THF). The resulting solution was stirred at room temperature for 20
min. BF3·Et2O (0.25 mL, 2.04 mmol) was added and the reaction
mixture stirred at room temperature for 20 h. The reaction mixture
was poured into saturated aqueous NaHCO3 (20 mL) and extracted
with CH2Cl2 (3 × 30 mL). The combined organic phases were dried
(MgSO4), filtered, and concentrated to give the crude material.
Purification by column chromatography (4/1 petroleum ether/ethyl
acetate → 1/1 petroleum ether/ethyl acetate → EtOAc) gave the title
compound 9f (125 mg, 89%) as a pink solid: mp 242−248 °C; Rf 0.31
(ethyl acetate); νmax (thin film)/cm−1 2944, 2845, 1638, 1586, 1518,
1461, 1412, 1349, 1261, 1242, 1186, 1055, 1048, 1093, 736; δH (400
MHz, CDCl3); 8.30 (1H, d, J = 9.2), 8.24 (1H, d, J = 8.1), 7.38 (1H, d,
J = 9.2), 7.20−7.12 (2H, m), 6.96 (1H, t, J = 7.8), 6.75 (1H, d, J =
8.1), 6.49 (1H, d, J = 7.8), 6.22 (1H, s), 4.70 (1H, ddd, J = 13.5, 7.1,
6.6), 4.03 (3H, s), 3.97 (3H, s), 3.61 (1H, ddd, J = 13.5, 7.1, 7.1), 3.34
(1H, ddd, J = 16.1, 7.1, 7.1), 3.07 (1H, ddd, J = 16.1, 7.1, 6.6); δC (100
MHz, CDCl3) 163.7 (CO), 158.5 (C), 154.4 (C), 138.0 (C), 135.6
(C), 130.7 (C), 128.9 (CH), 128.5 (CH), 127.2 (CH), 125.7 (CH),
123.9 (CH), 123.6 (CH), 119.3 (C), 116.7 (C), 113.7 (C), 111.2
(CH), 102.1 (CH), 55.9 (CH3), 55.7 (CH), 55.6 (CH3), 42.3 (CH2),
27.2 (CH2); HRMS (ESI) m/z calcd 346.1438 for C22H20NO3
(MH+), found 346.1440.
2-Methyl-6,7-dihydro-1H-pyrido[2,1-a]isoquinolin-4(11bH)-
one (9g; Table 4, Entry 7). Imine 1d (38 mg, 0.290 mmol) and 3-
methylbut-3-enoic acid 8g (34.8 mg, 0.348 mmol) were dissolved in
CH2Cl2 (2.9 mL). NEt(i-Pr)2 (69.3 mg, 93.5 μL, 0.536 mmol) and
T3P (13.8 mg, 0.435 mmol, 27.7 mg of a 50% solution in THF) were
added, and the reaction mixture was stirred at 45 °C for 1 h. TFA (165
mg, 111 μL, 1.449 mmol) was added and the reaction mixture stirred
at 45 °C overnight. The reaction was poured into saturated aqueous
NaHCO3 (5 mL) and extracted with CH2Cl2 (3 × 5 mL). The
combined aqueous layers were dried (MgSO4), filtered, and
concentrated to give the crude material. Purification by column
chromatography (2/1 petroleum ether/ethyl acetate) gave the title
compound 9g (48 mg, 78%) as a colorless oil: Rf 0.52 (ethyl acetate);
νmax (thin film)/cm−1 2974, 2936, 2909, 2851, 1670, 1623, 1415, 1299,
760; δH (400 MHz, CDCl3) 7.26−7.15 (4H, m), 5.88 (1H, app dq, J =
2.6, 1.4), 4.83−4.72 (2H, m), 3.00−2.75 (3H, m), 2.59 (1H, dd, J =
17.1, 4.9), 2.43−2.31 (1H, m), 1.99 (3H, s); δC (100 MHz, CDCl3)
165.4 (CO), 150.2 (C), 135.9 (C), 134.9 (C), 129.0 (CH), 126.7
(CH), 126.6 (CH), 125.6 (CH), 120.7 (CH), 54.3 (CH), 38.6 (CH2),
37.7 (CH2), 29.5 (CH2), 22.7 (CH3); HRMS (ESI) m/z calcd
214.1226 for C14H16NO (MH+), found 214.1223.
5,6,14,14b-Tetrahydroindolo[2′,3′:3,4]pyrido[2,1-a]-
isoquinolin-8(9H)-one (9d; Table 4, Entry 4). The compound was
synthesized using general DIA procedure E (at room temperature and
with BF3·OEt2 as the Lewis acid) from imine 1d (100 mg, 0.762
mmol) and carboxylic acid 8d (160 mg, 0.915 mmol). Purification by
column chromatography (ethyl acetate) gave the title compound 9d
(176 mg, 80%) as a light brown solid: mp decomposition noted at 205
°C (from EtOAc/MeOH); Rf 0.51 (ethyl acetate); νmax (thin film)/
cm−1 3063, 2953, 1603, 1454, 1226, 1216, 756, 738, 710; δH (400
MHz, CDCl3) 11.51 (1H, s), 7.50−7.43 (2H, m), 7.30−7.13 (5H, m),
7.04 (1H, ddd, J = 7.9, 7.0, 0.9), 6.02 (1H, s), 4.25 (1H, app dt, J =
12.8, 6.4), 3.67 (1H, dd, J = 20.7, 2.4), 3.47 (1H, dd, J = 20.7, 2.4),
3.48−3.39 (1H, m), 3.13−2.94 (2H, m); δC (100 MHz, CDCl3) 167.1
(CO), 137.7 (C), 137.0 (C), 135.4 (C), 128.5 (CH), 128.3 (C),
127.6 (CH), 126.2 (CH), 125.5 (C), 124.3 (CH), 121.8 (CH), 118.9
(CH), 118.3 (CH), 111.4 (CH), 105.0 (C), 54.9 (CH), 41.9 (CH2),
29.2 (CH2), 27.1 (CH2); HRMS (ESI) m/z calcd 289.1335 for
C19H17N2O (MH+), found 289.1334.
1-Vinyl-2,3,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-4-
(11bH)-one (9h; Table 4, Entry 8). The compound was synthesized
using general DIA procedure E (at room temperature and with BF3·
OEt2 as the Lewis acid) from imine 1d (100 mg, 0.762 mmol) and
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carboxylic acid 8h (170 mg, 0.915 mmol). Purification by column
chromatography (1/1 petroleum ether/ethyl acetate) gave the title
compound 9h (122 mg, 70%) as a clear, colorless oil, as a 5/1 (A/B)
mixture of diastereoisomers: Rf 0.39 (ethyl acetate); νmax (thin film)/
cm−1 2933, 2870, 1635, 1461, 1433, 1409, 1360, 1286, 1248, 916, 741;
δH (400 MHz, CDCl3) data for major diastereoisomer 7.26−7.10 (4H,
m), 5.53 (1H, ddd, J = 17.6, 10.1, 7.3), 4.97 (3H, m), 4.91 (1H, d, J =
3.4), 3.17−3.11 (1H, m), 2.88−2.67 (3H, m), 2.61 (1H, ddd, J = 18.0,
11.6, 7.0), 2.53 (1H, ddd, J = 18.0, 7.3, 2.8), 2.26−2.14 (1H, m), 2.09−
2.00 (1H, m), data for minor diastereoisomer 7.26−7.10 (4H, m), 6.05
(1H, ddd, J = 17.5, 10.3, 7.3), 5.26 (1H, dt, J = 17.5, 1.2), 5.24 (1H, dt,
J = 10.3, 1.1), 4.56 (1H, d, J = 7.3), 4.39 (1H, dt, J = 12.6, 5.6), 3.22−
3.16 (1H, m), 3.10−3.00 (1H, m), 2.88−2.67 (3H, m), 2.44−2.31
(1H, m), 1.97−1.78 (2H, m); δC (100 MHz, CDCl3) data for major
diastereoisomer 169.7 (CO), 135.8 (C), 134.4 (CH), 128.8 (CH),
126.5 (CH), 126.3 (CH), 126.2 (CH), 118.0 (CH2), 60.0 (CH), 42.3
(CH), 38.5 (CH2), 29.1 (CH2), 28.1 (CH2), 25.7 (CH2), one
quaternary carbon signal not observed, data for minor diastereoisomer
140.2 (CH), 136.5 (C), 134.9 (C), 128.5 (CH), 127.2 (CH), 126.1
(CH), 125.0 (CH), 116.4 (CH2), 59.6 (CH), 41.9 (CH2), 41.7 (CH),
30.6 (CH2), 28.5 (CH2), 26.2 (CH2), carbonyl signal not observed;
HRMS (ESI) m/z calcd 228.1383 for C15H18NO (MH+), found
228.1386.
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Text giving general experimental details and figures giving H
and 13C spectra of all novel compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail for R.J.K.T.: richard.taylor@york.ac.uk.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the EPSRC and the University of York for
postdoctoral support (W.P.U., EP/G068313/1; G.C., EP/
J016128/1), the University of York Wild Fund for a Ph.D.
bursary (C.K.), and Archimica for the generous donation of
T3P.
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