Photochemical Formation and Cleavage of C-N Bond

Article abstract of DOI:10.1021/ol503473c

A new photochemical method of C-N bond formation has been developed. A properly substituted trityl alcohol can cleave the benzylic C-O bond and replace it with a C-N bond which is stable under the irradiation conditions. The C-N bond can then be photochemically cleaved with the same light source when the nitrogen is protonated. (Chemical Presented).

Full text of DOI:10.1021/ol503473c

Letter
pubs.acs.org/OrgLett
Photochemical Formation and Cleavage of C−N Bond
Pengfei Wang,* Wenya Lu, Dattatray Devalankar, and Zhenying Ding
Department of Chemistry, University of Alabama at Birmingham, Birmingham, Alabama 35294, United States
S
* Supporting Information
ABSTRACT: A new photochemical method of C−N bond formation has been
developed. A properly substituted trityl alcohol can cleave the benzylic C−O
bond and replace it with a C−N bond which is stable under the irradiation
conditions. The C−N bond can then be photochemically cleaved with the same
light source when the nitrogen is protonated.
ight-promoted covalent bond formation and cleavage is
appealing to many different research areas in that
L
photoreactions can typically take place under mild conditions
without using any chemical reagents and can be precisely
controlled with a high spatial and temporal resolution. For
instance, photochemical bond cleavage reactions have been
utilized in developing various photolabile protecting groups
(PPGs). PPGs are crucial to a broad spectrum of applications
ranging from organic synthesis and dynamic studies in biology
to polymer science, surface patterning, and photolithographic
preparation of high density biochips.1−7 On the basis of the
excited state meta effect,8−11 we have recently developed a
series of salicyl alcohol-based carbonyl PPGs12−17 and trityl
alcohol-based hydroxyl PPGs (as in 2, eq 1).18−20 For example,
intermediate 8 could trap an amine (9) to form a photochemi-
cally inert covalent C−N bond in 10 (Scheme 1).
Scheme 1. Photochemical C−N Bond Formation
we have demonstrated that 3-dimethylaminotrityl group
(DMATr) protects both primary and secondary alcohols and
photochemically releases alcohols in high yields with high
photoefficiency.
To assess this idea, we first examined the irradiation of 7 in
the presence of n-butyl amine (9a).21 The reaction of 7 (6.0
mM) produced the best results in methanol.22 With 2 equiv of
n-butyl amine in methanol, the yields of 10a (R′ = n-butyl)
increased from 24% for 15 min irradiation to 37% for 60 min
irradiation. By increasing the amine to 13 equiv, 15 min
irradiation led to a 65% yield of 10a. However, the reaction
became less clean with increased irradiation time.
Encouraged by these results, we turned our attention to
photochemical C−N bond construction in aqueous solution. It
is known that release of ROH from protection of the water-
soluble analog of DMATr, i.e., release of ROH from 11, is clean
To expand the scope of structurally simple hydroxyl PPG
DMATr, we examined its application in the protection of
amino groups. First, we compared the photoreactions of 3a and
3b (eq 2). Under the same conditions, 3-phenyl-1-propanol
(4a) was released in 88% yield from 3a (5.0 mM in CD3OD)
after 8 min of irradiation while 3b was stable.21 Irradiation of
the compound 5 (3.0 mM in CH3OH) for 8 min resulted in
removal of the DMATr group on the hydroxyl group to release
1
the alcohol 6 in 73% of yield based on H NMR analysis,
consistent with the 72% isolated yield (eq 3).
These results suggest that the DMATr PPG on amino groups
is photochemically inactive under the irradiation conditions for
releasing alcohols. Thus, we hypothesize that irradiation of 7
would cleave the C−O bond, and the resulting tritylium
Received: December 1, 2014
Published: December 18, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
and fast in aqueous solution (eq 4).20 Recent Laser Flash
Photolysis (LFP) studies by Wan et al. indicate that
yields, respectively (Table 1, entries 7 and 9), better than when
using an excess of amine (Table 1, entries 6 and 8).
The photochemically stable benzylic C−N bond in 13 can
actually be converted to a photolabile bond and cleaved
photochemically with the same light source. For example,
irradiation of 13a (1.0 mM in D2O/CD3OD 4:1 or 5.0 mM in
CD3OD) in the presence of 3 equiv of HCl cleanly cleaved the
C−N bond and released 9a. In control experiments, without
irradiation, the acidified solution of 13a remained unchanged at
40 °C even after 60 min.
photocleavage of the benzylic C−O bond of 11 occurs within
a laser pulse of 29.6 ns;23 we anticipated that cleavage of the
C−O of 12 and the subsequent C−N bond formation will also
be clean and fast in aqueous media.
Photocleavage of C−N was further confirmed with DMATr-
protected amines (10b and 10c, Scheme 2). Thus,
Scheme 2. Photochemical Cleavage of C−N Bond21
We first irradiated 12 (10.0 mM in D2O) alone for 40 min
without the presence of an amine, and no perceptible change in
1
the H NMR spectrum could be detected. However, in the
presence of 2 equiv of n-butyl amine (9a), irradiation for 20, 40,
and 70 min led to 13a in 59%, 53%, and 45% yield, respectively
(Table 1, entry 1). By changing the ratio of 12/9a to 2:1 ([12]
Table 1. Photochemical C−N Bond Formation in Water
preirradiation treatment of 10b with 1 equiv of TFA or HCl
1
led to 14b as clearly evidenced by H NMR analysis. In the
ammonium salt 14, the C−N bond is thermally stable. Control
experiments showed that the C−N bond in 10a remained
stable with an excess amount of HCl (5−160 equiv in
methanol) at 40−55 °C without irradiation. Irradiation of 14b
for only 6 min resulted in release of the amine 15b in 81%
(with HCl) and 82% (with TFA) yield, respectively.24,25
In control experiments, irradiation of 10b (5.0 mM in
CD3OD) in the absence of any acids for 10 min did not show
any perceptible release of 4-methoxyphenethylamine 15b, in
agreement with observations from the photoreactions of 3b and
6 (eqs 2 and 3). In the presence of 1 equiv of HCl, the amine
15c was released from 10c in 86% yield and 6-amino-1-hexanol
from 6 in 77% yield. Since only a stoichiometric amount of
proton is needed to facilitate the C−N cleavage, the acidic
conditions are mild enough to be compatible with the acid-
sensitive protecting groups in 15c.
In summary, we have developed a new photochemical C−N
bond formation reaction. The new chemistry should be
potentially useful in many research areas such as protein
labeling and macromolecule cross-linking. Moreover, the
photochemically formed C−N bond can be converted to a
photolabile bond through protonation of the nitrogen and
cleaved photochemically with the same light source.
ab
,
ab
,
ab
,
[12]/
13
13
13
entry RNH2
mM
12/9
20 min
40 min
70 min
1
2
3
4
5
6
7
8
9
9a
9a
9a
9a
9a
9b
9b
9c
9c
10.0
10.0
20.0
20.0
20.0
20.0
20.0
20.0
20.0
1:2
2:1
1:2
2:1
5:1
1:2
2:1
1:2
2:1
59%
45%
62%
67%
60%
−
53%
45%
81%
78%
67%
68%
81%
63%
74%
45%
40%
75%
72%
59%
−
−
−
−
−
−
−
a
Irradiation with a 450 W medium pressure mercury lamp without
deaeration. Yield determined by H NMR analysis with an internal
standard.
b
1
= 10.0 mM), the yield of 13a formation after 20, 40, and 70
min of irradiation changed to 45%, 45%, and 40%, respectively
(Table 1, entry 2). When a large excess of 9a was used (i.e., 12/
9a = 1:20), 20 min irradiation led to a 56% yield of 13a, similar
to the yield obtained with only 2 equiv of 9a. A longer
irradiation time did not improve the yield. By increasing the
concentration of 12 to 20.0 mM, the yields of 13a increased
(Table 1, entries 3−5). It appeared that irradiation for 40 min
produced the best results. Extension of the irradiation time after
40 min (Table 1, entries 1−5) or increasing the 12/9a ratio to
5:1 ([12] = 20.0 mM) could not further improve the yield of
13a (Table 1, entry 5). We then irradiated 12 (20.0 mM) for 40
min in the presence of sodium glycinate (9b) and Ac-L-Lys-
NHMe (9c) (Table 1, entries 6−9). With the 12/9 ratio at 2:1,
the corresponding 13b and 13c were obtained in 81% and 74%
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, full characterization, and NMR
spectra of new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: wangp@uab.edu.
Notes
The authors declare no competing financial interest.
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Organic Letters
Letter
ACKNOWLEDGMENTS
We thank NSF (CHE 1404063) and ACS PRF (51827-ND7)
for financial support.
■
REFERENCES
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(21) Irradiation with a 450 W medium pressure mercury lamp with a
Pyrex filter sleeve in a Honovia photoreaction box without deaeration.
1
The yield was determined by H NMR spectroscopy analysis unless
indicated otherwise.
(22) A complex mixture was obtained when the same reaction was
carried out in DMF, MeCN, THF, diethyl ether, or acetone. The
reaction of 7 in pure 1-butylamine led to <10% conversion. In
methanol, the reaction of 3a with amine showed similar reactivity.
(23) Wang, Y.-H.; Wan. P. Unpublished results.
(24) With 1.2 equiv of acetic acid, the conversion of 10b in the
photoreaction was only 40%.
(25) Without using HCl, irradiation of 10 (5 mM in CD3OD) with
0.5% of CHCl3 (v/v) for 10 min also resulted in effective cleavage of
the C−N bond. Presumably, HCl was generated in situ from methanol
and chloroform upon irradiation. We examined several acid-promoted
reactions by using light-generated acid from CHCl3/MeOH. For
example, irradiation of 3,4-dihydro-2H-pyran (DHP) in methanol
showed no sign of reaction; however, in the presence of chloroform,
under the same irradiation conditions, DHP was converted to the
corresponding THP-OMe. If irradiation was stopped before complete
conversion of DHP and the reaction mixture was kept in the dark, the
remaining DHP slowly converted to the THP-OMe product.
Irradiation of CHCl3/MeOH first and then mixing with DHP in the
dark also led to clean production of THP-OMe. In another example,
the light-generated acid removed MMTr to release alcohol in excellent
yields.
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