Photochemical Cleavage of Benzylic C-N Bond to Release Amines

Article abstract of DOI:10.1021/acs.joc.6b00508

The 3-(diethylamino)benzyl (DEABn) group has been studied for releasing primary, secondary, and tertiary amines by direct photochemical breaking of the benzylic C-N bond. While photochemical release of primary and secondary amines provides high yields in

Full text of DOI:10.1021/acs.joc.6b00508

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Article
Photochemical Cleavage of Benzylic C-N Bond to Release Amines
Pengfei Wang, Dattatray A. Devalankar, and Wenya Lu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00508 • Publication Date (Web): 26 May 2016
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Photochemical Cleavage of Benzylic C-N Bond to
Release Amines
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Pengfei Wang,* Dattatray A. Devalankar, and Wenya Lu
Department of Chemistry, University of Alabama at Birmingham, 901 14th Street South, Birmingham,
AL 35294
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wangp@uab.edu
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
ABSTRACT The 3-diethylaminobenzyl (DEABn) group has been studied for releasing primary,
secondary, and tertiary amines by direct photochemical breaking of the benzylic C-N bond. While
photochemical release of primary and secondary amines provide high yields in methanol, release of
tertiary amines in MeCN/water can improve yields and reduce the undesired dealkylation side reaction.
INTRODUCTION
Photochemical removal of protecting groups utilizes light as a traceless reagent in the chemical
process. This approach is attractive to a wide range of research areas due to the unique advantages it
offers.1-11 Growing interests in using photolabile protecting groups (PPG) in basic and applied research
has generated an increasing demand for more PPGs to complement existing ones. The past several
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decades have witnessed tremendous efforts in developing new PPGs and creative applications of PPGs.
Despite the progress, efficient, fast, and direct release of amines remains challenging.1 There are only a
few examples of directly releasing amines photochemically, for instance, from phenacyl anilinium
salts,12-14 or in the photochemical reaction of generating o-quinone methides.15,16
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We have recently demonstrated that the 3-dimethylamino-trityl (DMATr) aminium salts release
simple primary amines in both organic and aqueous solutions.17 Most recently, Literak, Klan, and
coworkers have conducted detailed studies on release of various primary, secondary, and tertiary amines
from their corresponding 4-hydroxyphenacyl (pHP) aminium salts in aqueous solutions.18 The pH of
irradiated solutions plays a pivotal role in the amine-release process from pHP. While the pHP group is
effective for elementary primary and secondary aliphatic amines at or below physiological pH, release
of tertiary amines seems to be problematic.
We have recently reported that 3-diethylaminobenzyl group (DEABn),19 which was designed on the
basis of the excited state meta effect,20-23 released various alcohols (including primary, secondary, and
tertiary alcohols) efficiently in high chemical yields (Scheme 1). Thus starting with commercially
available 3-aminobenzyl alcohol 1, it takes two steps to synthesize the PPG reagent 2 (DEABn-Cl). Its
reaction with alcohol ROH results in the corresponding ether 3 (ε308nm (MeCN) = 2900 M−1cm−1) in high
yields. UV irradiation can release primary, secondary, and tertiary alcohols from DEABn protection in
high chemical and photochemical efficiencies. The DEABn PPG differs from the known 3,5-dimethoxy-
benzyl (DMBn) PPG which was also based on the meta effect.24 The latter is known for only releasing
good leaving groups such as carboxylate, carbonate, and carbamate. Herein we demonstrate a new
photochemical reaction if DEABn that can release amines (including primary, secondary, and tertiary
amines) effectively.
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Scheme 1. New Bn-type PPGs Releasing Alcoholsa
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aReagents and conditions: (a) Na2HPO4, EtI, 69%; (b) SOCl2, 98%; (c) NaH, Bu4NI, ROH, 86-98%; (d)
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h, 81-98%
RESULTS AND DISCUSSION
With the PPG reagent diethylaminobenzyl chloride (DEABn-Cl, 2), the PPG was installed onto the
primary and secondary amines (4a-e) under mild conditions to provide the caged amine 5a-e (Table 1).
For primary and secondary amines, the release of amines can take place in methanol. For example,
irradiation of 5a in CD3OD for 8 min led to 4a being released in 30% yield along with 56% un-reacted
5a.25 Irradiation for 15 min resulted in a complex mixture; the amine 4a was released in a lower yield
along with some un-identified byproducts in spite of the increased conversion of 5a to 73%. The
photoreaction of 5a in other solvents (such as acetonitrile, acetonitrile/water, and DMSO) did not
produce better results than in methanol. However, we noticed that there was a difference in the reaction
efficiency in deuterium solvent and in protium solvent. While the conversion of 5a in CD3OD was 73%,
it increased to 90% in CH3OH under the same irradiation conditions. This solvent isotope effect suggests
that photochemical cleavage of the C-N bond is probably facilitated by stabilizing the partially negative
charge developed at the nitrogen atom through hydrogen bonding with solvent molecules in the
transition state. Based on this hypothesis, we infer that addition of a protonic acid should facilitate
photocleavage of the C-N bond by converting the poor amide leaving group into a better amine leaving
group through protonation.
Table 1. Photochemical Cleavage of C-N Bond to Release Primary and Secondary Amines
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entry
1
Amine (4)
yield of 5 (%)a
(4a) 62b
yield
of
released 4 (%)c
NH2(CH2)18H
81d
2
3
66
95
98d
94e,f
(4b)
(4c)
90d
96e
4
5
88
92
75d (70g)
(4d)
(4e)
72d
aThe amine 4, PPG reagent 2, NaI, and K2CO3 in acetone at 40-50 C. The amine 4a, PPG reagent 2,
o
b
and Bu4NI in DCM/DMF at 35 oC. A 5.0 mM solution in the presence of AcOH (6.0 eq) in a specified
c
solvent in 5 mm NMR tubes was irradiated for 15 min with a 450W medium pressure mercury lamp
equipped with a Pyrex filter sleeve (>300 nm) without deaeration. The yields were determined by
proton NMR with an internal standard and isolated yields are in parenthesis. dIn CD3OD. eIn D2O. f10.0
mM solution. gIn CH3OH.
We examined photoreaction of 5a (pKa of the protonated amine ~10) in the presence of acetic acid
(pKa = 4.76).25 With the amount of acetic acid raised from one equiv to six equiv, complete conversion
of 5a was achieved in 15 min, and the yield of the released amine product increased from 66% to 81%.
Further increase of the amount of acetic acid up to 30 equiv did not significantly change the yield of the
released amine (i.e., 83%). With stronger acids such as trifluoroacetic acid (TFA, pKa = -0.25), acid-
enhanced amine releases were also observed with 1-10 equiv of TFA. However, with 30 equiv of TFA
or six equiv of HCl (pKa = -8.0), the amine-releasing process was significantly diminished, leading to
the yield of the corresponding aminium of 4a in only 42%, and 8%, respectively. Presumably,
protonation at the diethylamino group (pKa ~5) suppresses the photocleavage of the benzylic C-N bond.
1
In H NMR analysis of the pre-irradiation reaction solution of 5, downfield shifting of the benzylic
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methylene signal and the aromatic hydrogens is indicative of protonation at the respective aliphatic and
aromatic amino group.
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Similar acid-enhanced release of amines was confirmed with other protected primary and secondary
amines (Table 1, entries 2-5). For example, 5b (ε310nm (MeOH) = 2800 M−1cm−1), in the presence of acetic
acid (6 eq), released the aminium salt of 1-adamantanamine cleanly in 98% yield in CD3OD ( = 0.14)
(Table 1, entry 2). The aminium salts of secondary amines (4c-4e) were also released in good yields
under the same acidic conditions (Table 1, entries 3-5). For example, 5d (ε310nm (MeOH) = 2400 M−1cm−1)
released the salt of di-n-octylamine (4d) in 75% yield in CD3OD ( = 0.09). In a run in the presence of
acetic acid (6 eq) in CH3OH, the secondary amine 4d was isolated in 70% yield (after derivatizing with
FmocCl to facilitate separation). The relatively higher yield of 4b (compared with other amines) can
probably be attributed to the lack of germinal hydrogen at C-1, which might prevent potential SET-
originated side reactions of amines under the irradiation conditions (for the mechanism see Scheme 2,
Pathway B). It is noteworthy that the yield of releasing amines can be further improved in deaerated
solutions, especially for the reactions carried out in the absence of protonic acid. However, control
experiments showed that oxygen did not play a role in influencing the yield of releasing alcohols and
acids from their DEABn protection, which suggests that oxygen probably enhances undesired photo-
oxidation of amines. Photochemical release of protonated amines 5 from their 3-diethylaminobenzyl
aminium salts can also take place in a water solution. For example, the aminium salt 6b, prepared from
5b and one equiv of DCl dissolved in D2O (10.0 mM) and irradiated for 30 min, led to the
corresponding deuterated aminium salt of 4b in 94% yield.25 The aminium salt 6c (5.0 mM in D2O),
prepared in the same manner, led to the corresponding deuterated aminium salt of 4c in 96% yield upon
30 min of irradiation.25
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For the tertiary amines, the same method was used to install the DEABn group and high yields were
obtained, i.e., 88% from N,N-dimethyloctadecylamine (4f) to 5f and 93% from triethylamine (4g) to its
aminium salt 5g. The photoreaction conditions are different from releasing primary and secondary
amines. Thus, without using a protonic acid, irradiation of 5f (ε320nm (MeOH) = 1600 M−1cm−1) in CD3OD
for 8 min released 4f.D+ in 67% yield along with the demethylated byproduct 4e.D+ in 26% yield (eq 1
and Table 2, entry 1). The PPG part was converted mainly into the ether 7 (29%) and the reduced
product 8 (40%). With 15 min of irradiation in CD3OD, the yields of 4f.D+ and 4e.D+ changed to 62%
and 33%, respectively (Table 2, entry 2). Switching solvents to CH3OH did not affect product
distribution significantly. Irradiation of 5f in CH3OH for 15 min released 4f.H+ and 4e.H+ in 62% and
30% yield, respectively (Table 2, entry 3). The yields were confirmed by the isolated yields of 4f and 4e
(as its Fmoc derivative) in 63% and 30%, respectively (Table 2, entry 3). The structure of 8 was
confirmed by comparison with the authentic sample (See Experimental Section).
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Table 2. Photoreaction of 5f in Methanol
salt
Solvent
Irradiation
time (min)a
8
Yield of
4f (%)b
67
Yield of
4e (%)b
26
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5f
5f
5f
CD3OD
CD3OD
CH3OH
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62(63)c
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30(30)d
15
a5.0 mM irradiated in 5 mm NMR tubes with a 450W medium pressure mercury lamp equipped with a
Pyrex filter sleeve without deaeration. The yields were determined by proton NMR with an internal
b
standard and isolated yields are in parenthesis. Released as the corresponding aminium. cIsolated as 4f.
dIsolated as the Fmoc derivative.
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Contrary to the high yields obtained with primary and secondary amines in water solution, irradiation
of 5f and 5g (5 mM in D2O) was less efficient (Table 3). For example, irradiation of 5g for 10, 20, and
30 min led to 4g.D+ in 32%, 56%, and 67% yield respectively, along with the aminium salt of
diethylamine (10) in 12%, 20%, and 23%, respectively (Table 3). Acetaldehyde (11) was also observed
in 7% yield at 10 min increasing to 14% yield at 30 min, along with its hydrate (12) increasing from 4%
at 10 min to 10% at 30 min. In this reaction, the compound 8 was observed along with other
unrecognized products originating from the PPG moiety.
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Table 3. Photochemistry of 5g in water
5g(%) 9(%)
4g.D+(%)
10(%)
12
11(%)
7
12(%)
10 min
20 min
30 min
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67
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For the photoreaction of the caged tertiary amines (exemplified with 5f), we postulated that the initial
step would lead to the C-N bond cleavage and formation of the desired tertiary amine 4f and the PPG
benzylic cation I (Scheme 2). There could be multiple possible photochemical and thermal reaction
pathways starting from the pair of 4f and I under the reaction conditions. For example, quenching of I
with methanol would result in the ether 7. The released deutron would deutronate 4f to provide the salt
4f.D+ (Pathway A). A competing process would likely involve electron transfer between 4f and the
benzylic cation I to produce the radical cation II and the benzyl free radical III. The intermediate II
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could also be formed through SET between 4f and molecular oxygen under the irradiation reaction
conditions. Starting from here, the reaction pathway could be further diverted into two directions (i.e.,
Pathway B and C), depending the reaction conditions such as the solvent. Pathway B would involve
hydrogen abstraction of III from II, leading to formation of the reduced product 8 and the iminium
intermediate IV. Solvoylsis of IV would eventually generate the dealkylated product 4e.D+. Pathway C
would involve deuterium abstraction from the solvent by both II and III separately, leading to 4f.D+ and
8, respectively.
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Scheme 2. Mechanism of Photolysis of 5f
Formation of an iminium intermediate and thus converting a tertiary amine to the corresponding
secondary amine is known in the literature.26-33 A recent example is the observation of diethylamine and
acetaldehyde formation in the release of triethylamine from its 4-hydroxyphenacyl aminium salt in
aqueous solutions.18 A mechanism involving UV-initiated SET from the tertiary amine to the PPG
moiety followed by a subsequent reaction sequence similar to the pathway B postulated in Scheme 2
might also operate.
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Based on this working mechanism, we inferred that by using a solvent with better hydrogen donating
ability than methanol, pathway C would be enhanced, improving release of the tertiary amine and
minimizing production of the secondary amine byproduct. Thus we anticipated that switching solvent
from methanol (DEC-H = 92 kcal/mol) to acetonitrile (DEC-H = 86 kcal/mol)34 would improve the ratio of
product to byproduct. Indeed, the photoreaction of 5f in MeCN/water became more chemically efficient
with fewer byproducts. Irradiation of 5f in CD3CN/D2O (9:1) for 15 min led to 4f.D+ in 83% yield ( =
0.18) along with the reduced production of 4e.D+ in 12% yield (Table 4, entry 1). In a larger scale run,
irradiation of 5f under the same conditions in CH3CN/H2O (9:1) led to 4f in 85% isolated yield (Table 4,
entry 2).35 In pure acetonitrile, the yield of 4f.D+ was 80% while the formation of the 4e.D+ was
completely eliminated (Table 4, entry 3); the main product derived from the PPG portion was the N-[(3-
diethylaminophenyl)methyl]acetamide in 30% yield. The high yield of tertiary amine product in
MeCN/water was then confirmed with the reaction of 5g CD3CN/D2O (9:1); the triethylamine salt was
released in 91% yield (Table 4, entry 4). As expected, the solvent isotope effect was not significant, and
the presence of six equiv of acetic acid in the solution of 5f did not change the reaction yields. These
results suggest that addition of acid to 5a-5e probably facilitates photocleavage of the C-N by converting
the amino group into a good leaving group instead of preventing the SET-related side reactions of the
released amine.
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Table 4. Photoreaction of 5f and 5g in Different Solvents
salt
Solvent
Irradiation
time (min)a
Yield of
Yield of
3o
amine
2o
amine
(%)b
(%)b
1
2
3
4
5f
5f
5f
5g
CD3CN/D2O (9:1)
CH3CN/H2O (9:1)
CD3CN
83
(85)c
12
NDd
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15
80
0
NDd
CD3CN/D2O (9:1)
91
a5.0 mM irradiated in 5 mm NMR tubes with a 450W medium pressure mercury lamp equipped with a
Pyrex filter sleeve without deaeration. The yields were determined by proton NMR with an internal
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b
standard and isolated yields are in parenthesis. Released as the corresponding aminium. cIsolated as 4f.
3
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5
d ND = not determined.
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It is also worth noting that the PPG-incorporated acetamide 13 is photochemically stable under the
irradiation conditions. Despite the fact that the acetamide 14 is a better leaving group than amine, there
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was no perceptible reaction detected by H NMR analysis in the reaction solution of pure 13 irradiated
in methanol or MeCN/water with or without the presence of acetic acid (1-30 equiv) (Scheme 3).
Presumably, with the carbonyl group’s presence, a SET process between the aromatic amino group and
the carbonyl and the subsequent decay of the intermediate 15 back to 13 serves as an effective internal
filtering process (Scheme 3). This hypothesis is in agreement with our earlier observations that release
of an acid from DEABn protection is less efficient than release of an alcohol. In releasing acid, a similar
SET process might also be operative.36,37
Scheme 3. Photochemical Inertness of Acetamide
In summary, we demonstrated that the DEABn PPG can effectively release primary, secondary, and
tertiary amines by direct breaking of C-N bond photochemically. While photochemical release of
primary and secondary amines provide high yields in methanol, release of tertiary amines in
MeCN/water can improve yields and reduce the undesired dealkylation side reaction.
Experimental Section
General. Organic solutions were concentrated by rotary evaporation at ca. 12 Torr. Flash column
chromatography was performed employing 230-400 mesh silica gel. Thin-layer chromatography was
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performed using glass plates pre-coated to a depth of 0.25 mm with 230-400 mesh silica gel
impregnated with a fluorescent indicator (254 nm). Infrared (IR) data are presented as frequency of
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13
absorption (cm-1). Proton and carbon-13 nuclear magnetic resonance (1H NMR or C NMR) spectra
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were recorded on 300, 400 and 700 MHz NMR spectrometers; Chemical shifts are expressed in parts per
million (δ scale) downfield from tetramethylsilane and are referenced to residual protium in the NMR
solvent (CHCl3: δ 7.26). Data are presented as follows: chemical shift, multiplicity (s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet and/or multiple resonances), coupling constant in Hertz
(Hz), integration. HRMS was conducted with ESI ionization method and with TOF mass analyser.
Materials. Anhydrous solvents Tetrahydrofuran (THF), dimethylformamide (DMF), and
dichloromethane (DCM) were used without distillation. Solvents for workup and column
chromatography, such as petroleum ether (PE), ethyl acetate (EA), methanol (MeOH), and triethylamine
(TEA), and other chemicals were obtained from commercial vendors and used without further
purification.
N,N-diethyl-3-((octadecylamino)methyl)aniline (5a): To the solution of 3-(N,N-diethylamino)benzyl
chloride 2 (0.1 gm, 0.507 mmol) and octadecan-1-amine 4a (0.82 gm, 3.04 mmol) in DCM/DMF (2 mL:
0.5 mL) was added tetrabutylamomium iodide (56 mg, 0.151 mmol). The mixture was stirred at 35
4 days. The reaction mixture was then concentrated and the residue was purified with flash column
̊C for
chromatography (from DCM/EtOAc 1:1 to EtOAc) to provide 5a (136 mg, 62%) as a yellow oil. Rf 0.4
(DCM/MeOH/Et3N 1:1:0.01); 1H NMR (300 MHz, CDCl3) δ 7.16 (t, J = 7.9 Hz, 1H), 6.63 (d, J = 1.7
Hz, 1H), 6.60-6.55 (m, 2H), 3.72 (s, 2H), 3.34 (q, J = 7.0 Hz, 4H), 2.63 (t, J = 7.2 Hz, 2H), 1.55-1.45
(m, 1H), 1.25 (m, 32H), 1.15 (t, J = 7.0 Hz, 6H), 0.87 (t, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
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148.1, 141.8, 129.3, 115.4, 111.7, 110.6, 54.8, 49.7, 44.4, 32.0, 30.3, 29.8, 29.7, 29.5, 27.5, 22.8, 14.2,
12.7; IR (neat) 2921, 2851, 1601, 1580, 1496, 1456, 1394, 1374, 1355, 1270, 1199, 1176, 1145, 1118,
1094, 1076, 1024, 989, 909, 849, 768, 732, 693, 434; HRMS (ESI) m/z: calc for C29H55N2 (M+H)
431.4365, found 431.4367.
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N-(3-aminobenzyl)adamantan-1-amine (5b): To the solution of 2 (0.5 g, 2.5 mmol) and 1-adamantamine
4b (0.383 g, 2.5 mmol) in acetone was added NaI (95 mg, 0.63 mmol) and potassium carbonate (0.42 g,
3.04 mmol). The mixture was stirred at 45 ̊C for 24 h and was then concentrated. The residue was
purified with flash column chromatography (PE/EA 7:3 to EA) to provide 5b (0.52 g, 66%) as a
colorless liquid. Rf = 0.45 (DCM/ MeOH/Et3N 1:1:0.01); 1H NMR (300 MHz, CDCl3) δ 7.14 (t, J = 8.0
Hz, 1H), 6.65-6.53 (m, 3H), 3.70 (s, 2H), 3.33 (q, J = 7.0 Hz, 4H), 2.08 (m, 3H), 1.72-1.602 (m, 13H),
1.14 (t, J = 7.0 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 147.9, 142.4, 129.3, 115.4, 111.9, 110.4, 50.9,
45.7, 44.2, 42.7, 36.7, 29.6, 12.6; IR (neat) 2967, 2902, 2846, 1601, 1579; HRMS (ESI) m/z: calc for
C21H33N2 (M+H) 313.2644, found 313.2640.
3-((4-Benzylpiperidin-1-yl)methyl)-N,N-diethylaniline (5c): To the solution of 2 (0.3 g, 1.52 mmol) and
4-benzylpiperidine 4c (0.266 g, 1.52 mmol) in acetone was added NaI (57 mg, 0.38 mmol) and
potassium carbonate (0.210 g, 1.52 mmol). The reaction mixture was stirred at 40 ̊C for 24 h and then
concentrated. The residue was purified by flash column chromatography (PE/EA 8:1 to 1:1) to provide
5c as a colorless liquid (0.487 g, 95%). Rf = 0.5 (DCM/MeOH/Et3N 1:1:0.01); 1H NMR (300 MHz,
CDCl3) δ 7.28-7.24 (m, 2H), 7.19-7.10 (m, 4H), 6.62-6.54 (m, 3H), 3.42 (s, 2H), 3.32 (q, J = 7.0 Hz,
4H), 2.90-2.86 (m, 2H), 2.51 (d, J = 6.8 Hz, 2H), 1.88 (td, J = 2.2, 11.6 Hz, 2H), 1.62-1.60 (m, 2H),
1.60-1.45 (m, 1H), 1.35-1.28 (m, 2H), 1.14 (t, J = 7.0 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 147.7,
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140.8, 139.4, 129.0, 128.8, 128.0, 125.6, 116.4, 112.6, 110.4, 63.9, 53.7, 44.3, 43.2, 37.2, 32.2, 12.5; IR
(neat) 3025, 2967, 2920, 2846, 2795, 2750, 1600, 1579, 1494; HRMS (ESI) m/z: calc for C23H33N2
(M+H) 337.2644, found 337.2642.
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3-((Dioctylamino)methyl)-N,N-diethylaniline (5d): To the solution of 2 (0.4 g, 2.03 mmol) and di-n-
octylamine 4d (0.4 g, 1.65 mmol) in acetone was added NaI (62 mg, 0.41 mmol) and potassium
carbonate (0.229 g, 1.65 mmol). The mixture was stirred at 40 ̊C for 12 h and was then concentrated.
The residue was purified with flash column chromatography (PE/EA 8:2) to provide 5d as a colorless
liquid 0.581 g (88%). Rf = 0.3; 1H NMR (300 MHz, CDCl3) δ 7.12 (t, J = 7.9 Hz, 1H), 6.71 (s, 1H),
6.59-6.53 (m, 2H), 3.49 (s, 2H), 3.33 (q, J = 7.0 Hz, 4H), 2.39 (t, J = 7.5 Hz, 4H), 1.45 (m, 4H), 1.25 (m,
20H), 1.15 (t, J = 6.9 Hz, 6H), 0.87 (t, J = 6.8 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 147.9, 141.4,
128.9, 116.3, 112.5, 110.5, 59.2, 54.0, 44.5, 32.0, 29.8, 29.5, 27.7, 27.3, 22.8, 14.2, 12.8; IR (neat) 2955,
2923, 2853, 2794, 1601, 1580, 1495; HRMS (ESI) m/z: calc for C27H51N2 (M+H) 403.4052, found
403.4049.
N,N-diethyl-3-((methyl(octadecyl)amino)methyl)aniline (5e): To the solution of 2 (0.25 g, 1.27 mmol)
and N-methyl octadecylamine 4e (0.360 g, 1.27 mmol) in acetone was added NaI (47 mg, 0.317 mmol)
and potassium carbonate (0.21 g, 1.52 mmol). The mixture was stirred at 50 ̊C for 24 h and was then
concentrated. The residue was purified with flash column chromatography (PE/EA 7:3 to EA) to provide
5e as a colorless liquid 0.514 g (yield 92%). Rf = 0.56 (DCM: MeOH 9:1); 1H NMR (300 MHz, CDCl3)
δ 7.14 (t, J = 7.9 Hz, 1H), 6.65-6.56 (m, 3H), 3.42 (s, 2H), 3.33 (q, J = 7.0 Hz, 4H), 2.34 (t, J = 7.6 Hz,
2H), 2.20 (s, 3H), 1.50 (m, 2H), 1.25 (m, 30H), 1.15 (t, J = 7.0 Hz, 6H), 0.88 (t, J = 6.9 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 147.8, 140.2, 128.9, 116.3, 112.5, 110.4, 62.9, 57.4, 44.2, 42.4, 31.9, 29.6,
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29.3, 27.5, 22.6, 14.1, 12.6; IR (neat) 2921, 2851, 2784, 1601, 1580, 1495; HRMS (ESI) m/z: calc for
C30H57N2 (M+H) 445.4522, found 445.4517.
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N-(3-(diethylamino)benzyl)-N,N-dimethyloctadecan-1-aminium chloride (5f): To the solution of 2
(0.400 g, 2.0 mmol) and N,N-dimethyl-n-octadecylamine 4f (0.725 g, 2.4 mmol) in acetone was added
NaI (15 mg, 0.10 mmol). The mixture was stirred at 40 C for 15 h and was then concentrated. The
̊
residue was purified with flash column chromatography (DCM/MeOH 9:1) to provide 5f as a colorless
liquid 0.910 g (88%). Rf = 0.4; 1H NMR (300 MHz, CDCl3) δ 7.22 (t, J = 7.4 Hz, 1H), 6.88 (s, 1H),
6.74-6.69 (m, 2H), 4.79 (s, 2H), 3.54-3.48 (m, 2H), 3.36 (q, J = 7.0 Hz, 4H), 3.33 (s, 6H), 1.80 (br, 2H),
1.34-1.25 (m, 30H), 1.16 (t, J = 7.0 Hz, 6H), 0.88 (t, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
148.4, 130.1, 128.2, 119.2, 116.1, 113.6, 68.6, 63.9, 50.3, 44.5, 32.1, 29.82, 29.76, 29.70, 29.6, 29.5,
29.4, 26.5, 23.2, 22.8, 14.2; IR (neat) 3384, 3045, 3015, 2962, 2914, 2847, 1602, 1578, 1500; HRMS
(ESI) m/z: calc for C31H59N2 (M-Cl) 459.4678, found 459.4682.
N-(3-(diethylamino)benzyl)-N,N-diethylethanaminium chloride (5g): To the Solution of 2 (0.4 g, 2.03
mmol) and triethyl amine 4g (1.69 mL, 12.1 mmol) in acetone was added NaI (15 mg, 0.10 mmol). The
mixture was stirred at 50 ̊C for 4 days and was then concentrated. The residue was purified with flash
column chromatography (PE/EA 7:3 to EA) to provide 5g (0.567 g, 93%) as a colorless liquid. Rf = 0.4
(DCM/MeOH 9:1); 1H NMR (300 MHz, CDCl3) δ 7.20 (t, J = 7.2 Hz, 1H), 6.73-6.70 (m, 2H), 6.60 (d, J
= 7.6 Hz, 1H), 4.52 (s, 2H), 3.44 (q, J = 7.0 Hz, 6H), 3.33 (q, J = 7.1 Hz, 4H), 1.46 (t, J = 7.1 Hz, 9H),
1.14 (t, J = 7.1 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 147.8, 129.8, 127.4, 117.9, 114.6, 113.1, 61.5,
52.4, 44.0, 12.1, 8.1; IR (neat) 3375, 2972, 1600, 1577, 1502, 1481; HRMS (ESI) m/z: calc for C17H31N2
(M+) 263.2487, found 263.2486.
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General procedure for photoreaction:
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Photoreaction in 5 mm NMR tube in deuterated solvent: To 5 mm NMR tubes was added 0.5 mL of the
stock solution of 5 (5.0 mM) with a micro syringe. The proper amount of acid was then added. One
NMR tube containing the solution was kept in the dark as a control. Another NMR tube was then bound
to the immersion well condenser of the photoreactor. A 450W medium pressure mercury lamp equipped
with a Pyrex filter sleeve (>300 nm) was used as the light source. After irradiation, an equal amount of
the internal standard solution (such as mesitylene) was added to both the control tube and the reaction
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tube. The conversion and yields of the photoreaction were then determined by H NMR analysis of the
photoreaction samples and the control sample with the internal standard. For photoreactions under inert
atmosphere, the reaction tube was bubbled argon for ~2 min through a long needle to exclude air.
Photoreaction in non-deuterated solvent: To a 5 mm NMR tube was added 0.5 mL of the stock solution
of 3-((dioctylamino)methyl)-N,N-diethylaniline 5d (5.0 mM) with a micro syringe. The proper amount of
acid was then added. One NMR tube containing the solution was kept in the dark as a control. Another
NMR tube was then bound to the immersion well condenser of the photoreactor. A 450W medium
pressure mercury lamp equipped with a Pyrex filter sleeve (>300 nm) was used as the light source.
After UV irradiation, the reaction solution and the control were transferred separately to respective vials,
and the solvent was removed under reduced pressure. The residue was redissolved in CDCl3 and an
equal amount of the internal standard solution (such as mesitylene) was added to both the reaction
mixture and the control. The conversion and yields were calculated based on integration of mesitylene
and the products.
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Photolysis of 3-((dioctylamino)methyl)-N,N-diethylaniline (5d) in methanol: The solution of 5d (40 mg,
0.1 mmol) with acetic acid (34 L, 0.6 mmol) in 20 mL of methanol was divided equally into 13 5 mm
NMR tubes. The tubes were bound to the immersion well condenser of the photoreactor and irradiated
for 15 min. After irradiation, the reaction solutions were combined and concentrated. The residue was
then subject to the standard procedure in acetonitrile/water (3:1) with Fmoc-Cl and sodium carbonate to
provide the Fmoc-protected amine S1 (32.8 mg, 70%) as a colorless oil after flash column (PE/EA 20:1)
purification. 1H NMR (300 MHz, CDCl3) δ 7.74 (d, J = 7.5 Hz, 2H), 7.57 (d, J = 7.5 Hz, 2H), 7.40-7.24
(m, 4H), 4.48 (d, J = 6.3 Hz, 2H), 4.22 (t, J = 6.3 Hz, 1H), 3.18 (t, J = 7.5 Hz, 2H), 3.02 (t, J = 7.5 Hz,
2H), 1.48 (m, 2H), 1.26-1.11 (m, 22H), 0.89-0.87 (m, 6H); 13C NMR (75 MHz, CDCl3) δ156.2, 144.4,
141.5, 127.6, 127.1, 124.9, 120.0, 66.7, 47.6, 47.3, 31.9, 29.5, 29.4, 28.8, 28.3, 27.0, 22.8, 14.2; IR (neat
) 2954, 2923, 2854, 1697, 1464; HRMS (ESI) m/z: calc for C31H46NO2 (M+H) 464.3529, found
464.3524.
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Photolysis of N-(3-(diethylamino)benzyl)-N,N-dimethyloctadecan-1-aminium chloride (5f) in methanol:
The solution of 5f (74 mg, 0.15 mmol) in 30 mL of methanol was divided equally into 20 5 mm NMR
tubes. The tubes were bound to the immersion well condenser of the photoreactor and irradiated for 15
min. After irradiation, the reaction solutions were combined and concentrated. The residue was then
subject to the standard procedure in acetonitrile/water (3:1) with Fmoc-Cl and sodium carbonate to
convert the secondary amine 4e to (9H-fluoren-9-yl)methyl methyl(octadecyl)carbamate S2. The
reaction solution was then concentrated and purified with flash column (PE/EA 20:1) to provide 4f (28.2
mg, 63%) and S2 (23.2 mg, 30%). For S2, 1H NMR (300 MHz, CDCl3) δ 7.77 (d, J = 7.4 Hz, 2H), 7.62
(m, 2H), 7.42 (t, J = 7.3 Hz, 2H), 7.28 (t, J = 7.3 Hz, 2H), 4.48 (d, J = 5.6 Hz, 1H), 4.42 (d, J = 6.7 Hz,
1H), 4.25 (m, 1H), 3.30 (m, 1H), 3.12 (t, J = 7.0 Hz, 1 H), 2.90 (d, J = 10.7 Hz, 3H), 1.06-1.63 (m), 0.90
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(t, J = 6.9 Hz, 3H);13C NMR (75 MHz, CDCl3) δ 156.2, 144.2, 141.3, 127.5, 126.9, 125.0, 124.8, 119.9,
66.9, 48.9, 47.4, 34.5, 31.9, 29.7, 29.6, 29.4, 29.3, 27.8, 27.5, 26.7, 22.6, 14.1; IR (neat) 2922, 2852,
1704, 1478; HRMS (ESI) m/z: calc for C34H52NO2 (M+H) 506.3998, found 506.3994. For N,N-diethyl-
3-(methoxymethyl)aniline (7), 1H NMR (300 MHz, CDCl3) δ 7.18 (t, J = 7.5 Hz, 1 H), 6.65-6.59 (m, 3
H), 4.40 (s, 2 H), 3.39-3.32 (m, 7 H), 1.15 (t, J = 7.2 Hz, 6 H); 13C NMR (75 MHz, CDCl3) δ 148.2,
139.3, 129.4, 115.0, 111.4, 111.2, 75.4, 58.1, 44.4, 12.7; IR (cm-1) 2969, 2926, 2870, 2818, 1601, 1580;
1496; HRMS (ESI) m/z: calc for C12H20NO (M+H) 194.1545, found 194.1544.
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N,N-diethyl-3-methylaniline (8): To the ice-water bath cooled solution of LiAlH4 (19 mg, 0.5 mmol) in
1.8 mL dry THF was added 2 (40 mg, 0.2 mmol) 0.2 mL of THF. The mixture was allowed to warm to
room temperature and stir overnight and was then quenched with 19 µL of water, 38 µL of 10% NaOH
(aq), and 57 µL of water. The crude product was concentrated and purified with flash column
chromatography (PE/EA 25:1) to provide 8 (16 mg, 49%) as a colorless oil. 1H NMR (300 MHz, CDCl3)
δ 7.12 (t, J = 7.1 Hz, 1H), 6.53-6.47 (m, 3H), 3.35 (q, J = 7.2 Hz, 4H), 2.32 (s, 3H), 1.16 (t, J = 7.2 Hz,
6H); 13C NMR (75 MHz, CDCl3) δ 148.1, 139.0, 129.3, 116.5, 112.8, 109.3, 44.4, 22.1, 12.8; IR (neat)
3044, 2967, 2927, 2870, 1599, 1579, 1496, 1467; HRMS (ESI) m/z: calc for C11H18N (M+H) 164.1439,
found 164.1436.
Photolysis of N-(3-(diethylamino)benzyl)-N,N-dimethyloctadecan-1-aminium chloride (5f) in
MeCN/H2O: (A) The solution of 5f (74 mg, 0.15 mmol) in 30 mL of MeCN/H2O (9:1) was divided
equally into 20 5 mm NMR tubes. The tubes were bound to the immersion well condenser of the
photoreactor and irradiated for 15 min. After irradiation, the reaction solutions were combined,
concentrated, and purified with flash column (PE/EA 20:1) to provide 4f (38 mg, 85%). (B) The solution
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of 5f (500 mg, 1.0 mmol) was dissolved in 250 mL of MeCN/H2O (9:1) in a 250 mL photoreactor
vessel. The reaction solution was irradiated for 60 min with stirring. After irradiation, the reaction
solution was concentrated. To the residue was added MeCN/H2O (90 mL, 3:1), Fmoc Cl (0.39 g, 1.5
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mmol) and Na2CO3 (0.21 g, 2.0 mmol), and reaction solution was stirred at room temperature for 19 h.
The reaction mixture was then concentrated and purified with flash column chromatography (PE/EA
9:1to DCM/MeOH 9:1) to provide 4f (0.21 g, 70%).
Quantum yield determination: A 5.0 mM solution of phenylglyoxylic acid (CD3CN/D2O 3:1) and a 5.0
mM solution of 5 in NMR tube were placed behind a standard 1 cm quartz UV cuvette contain the filter
solution.38 Filtered light centered at 312 nm was obtained by passing light from the 450 W medium
pressure mercury lamp through a solution of 2.0 mM K2CrO4 in a 5% K2CO3 aqueous solution.39,40 The
yields of photo reactions were determined by 1H NMR for every 15 min of irradiation.
ACKNOWLEDGMENT. We thank the NSF (CHE 1404063) for financial support. We also thank Z.
Ding for the contribution to the synthetic work.
1
Supporting Information Available: H and 13C NMR spectra of new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
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