Installation of photolabile carbonyl-protecting groups under neutral conditions without using any other chemical reagents

Article abstract of DOI:10.1002/ejoc.200800966

Methods of installing photolabile protecting groups for carbonyl compounds under neutral conditions without using any other chemical reagents are described. Wiley-VCH Verlag GmbH & Co. KGaA, 2009.

Full text of DOI:10.1002/ejoc.200800966

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200800966
Installation of Photolabile Carbonyl-Protecting Groups under Neutral
Conditions without Using Any Other Chemical Reagents
Pengfei Wang,*[a] Yun Wang,[a] Huayou Hu,[a] and Xing Liang[a]
Keywords: Carbonyl compounds / Protecting groups / Neutral conditions / Reagent-free reactions / Photolabile groups /
Solvent-free reactions
Methods of installing photolabile protecting groups for car-
bonyl compounds under neutral conditions without using any
other chemical reagents are described.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Thus, the reaction of 3-[(TBS)oxy]propanal (3a) with sal-
icyl alcohol 1 at 140 °C afforded the desired acetal 4a in
94% yield (Table 1, Entry 1), whereas the conventional pro-
cedures requiring an acid catalyst[2] led to considerable de-
composition of the aldehyde 3a, and the yield of 4a was
lower than 40%. The new protocol appeared to be a general
method for the protection of aldehydes. Some representative
aldehydes reacted with 1 smoothly at 140 °C and provided
the desired acetals 4 in excellent yields (Table 1). It is note-
worthy that solvent was typically not required. When a sol-
vent such as p-xylene was used, as anticipated, the reactions
became considerably slower. It took 2 h for the reaction of
3b and 1 to reach completion with 97% yield without p-
xylene, but 6.5 h to reach completion with 96% yield in a
0.05  solution of 3b in p-xylene. Prolonged heating at
140 °C increased the byproducts. Decomposition of acetal
4 at the reaction temperature seemed not to be a major
source of these byproducts because, for example, only less
than 5% of pure 4c decomposed after heating at 140 °C for
15 h. It was assumed that the byproducts were mainly from
decomposition of salicyl alcohol 1. Indeed, when only 1 was
subject to the reaction conditions, the same byproducts
were generated. Elevating of the reaction temperature above
140 °C accelerated the reaction rate, taking only 20 min for
the reaction of 3b and 2 equiv. of 1 to reach completion
with 97% yield at 180 °C (Table 1, Entry 2). However, the
rates of the side reactions also accelerated, leading to more
of the byproducts from the excess of 1, which could compli-
cate purification.
Introduction
Acid-catalyzed formation of 1,3-dioxane ring systems are
commonly applied to protect carbonyl groups in organic
synthesis.[1] Recently, we have demonstrated that derivatized
salicyl alcohols (such as 1 in Scheme 1) are useful in pro-
tecting carbonyl groups as robust photolabile protecting
groups (PPGs).[2] Similar to other 1,3-dioxane formation re-
actions, installation of these PPGs requires an acid cata-
lyst.[3]
Scheme 1. Photolabile carbonyl-protecting group.
One of the appealing features of PPGs is that they are
typically removed upon irradiation under neutral condi-
tions without using any chemical reagents. It will be of
interest if installation of PPGs could also be carried out
under green-chemistry conditions. Not only would such a
method provide an alternative access to the synthesis of
photosensitive acetals/ketals but it could also be valuable
for the protection of acid-sensitive carbonyl compounds.
Results and Discussion
Herein we report neutral protocols for synthesizing 1,3-
dioxanes from salicyl alcohol 1 or the quinone methide di-
mer 2 (derived from 1) with various aldehydes without
using any other chemical reagents.
To our delight, the unusual quinomethide dimer 2,[4] ser-
endipitously synthesized by treating 1 with phosphorus
pentoxide (P2O5) in toluene at 0 °C, also underwent thermal
reaction with aldehydes to provide acetals in excellent yields
(Table 1). Typically, the reactions of aldehydes with dimer 2
required a solvent (e.g. p-xylene) for a more homogeneous
phase at 140 °C. Without p-xylene, a homogeneous phase
could not be achieved even at 180 °C. The heterogeneous-
[a] Department of Chemistry, the University of Alabama at
Birmingham,
901 14th Street South, Birmingham, Alabama 35294, USA
Fax: +1-205-934-2543
E-mail: wangp@uab.edu
208
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Photolabile Carbonyl-Protecting Groups
Table 1. Formation of acetal 4 under neutral conditions.
Entry
Aldehyde
Yield of 4 (%)
Method A[a] Method B[b]
1
2
3-[(TBS)oxy]propanal (3a)
3-phenylpropanal (3b)[2]
94 (3 h)[c]
97 (2 h)
94 (4 h)
99 (2 h)
96 (6.5 h)[d]
97 (20 min)[e]
98 (9.5 h)
97 (6 h)
Scheme 2. Mechanism of acetal formation reaction.
3
4
5
6
4-phenoxybenzaldehyde (3c)[2]
m-anisaldehyde (3d)
2-ethylhexanal (3e)
96 (9.5 h)
99 (6 h)
99 (8.5 h)
93 (8 h)
ence of air and water. For example, addition of water to the
thermal reaction of 1 decreased the amount of 6, whereas
the amounts of 7 and 8 increased and kept at a 1:1 ratio.
When the reaction was carried out in the presence of air,
more 7 formed.
99 (8.5 h)
83 (8.5 h)
(E)-2-heptenal (3f)
[a] Aldehyde 3 (0.05 mmol) and salicyl alcohol 1 (0.1 mmol) heated
at 140 °C under argon without solvent. [b] Aldehyde 3 (0. 05 mmol)
and dimer 2 (0.05 mmol) in 1.0 mL of p-xylene heated at 140 °C.
[c] Aldehyde 3 (0.05 mmol) and salicyl alcohol 1 (0.1 mmol) heated
at 140 °C under argon with two drops of p-xylene. [d] In 1.0 mL of
p-xylene. [e] At 180 °C, no solvent.
phase reactions typically led to poor yields. For example,
the reaction between 2 and 3b at 180 °C without solvent
1
resulted in a maximal 45% yield of 4b in 1 h based on H
NMR analysis, and then the yield began to decrease due to
decomposition of 4b. In p-xylene, reaction of aldehydes with
dimer 2 at 140 °C seemed to be more efficient than with 1
(e.g. for 3b, 99% in 2 h with 2 vs. 96% in 6.5 h with 1 under
the same conditions) (Table 1, Entry 2). Interestingly, dimer
2 seemed to be more reactive in p-xylene than without it.
When dimer 2 was heated neat at 180 °C for 1 h, only less
than 5% of 2 reacted based on 1H NMR analysis. However,
more than 90% of 2 (0.02 mmol, in 25 µL of p-xylene) re-
acted at 180 °C within 1 h, and more than 60% of 2
Figure 1. Thermal reaction of 1 at 140 °C.
The current neutral protocols are not efficient in con-
(0.1 mmol, in 0.1 mL of p-xylene) reacted at 140 °C within verting ketones to ketals, and the yields were lower than
5 h. those of the aldehyde cases under the same conditions. For
We postulated that acetal 4 was formed from a cycliza- example, the maximal yield of the desired ketal from the
tion reaction of the aldehyde with the reactive quinone reaction of 4-phenylcyclohexanone with 1 was only 64%,
methide intermediate 5 generated in situ from the dehy- obtained after 5 h of heating at 140 °C.[5] The relative low
dration reaction of 1 or from the thermal decomposition of yields were rationalized as the result of slow cyclization be-
the dimer 2 (Scheme 2). The reaction between aldehyde 3 tween a ketone and the intermediate 5, leading predomi-
and 5 was much faster than the side reactions of 5. These nantly to competitive side reactions. In addition, the insta-
side reactions resulted in byproducts 6–8.
bility of ketals formed by 1 with different ketones could
The same byproducts were also obtained from heating 1 also contribute to the low yields. For example, 10% of the
neat at 140 °C, 2 in p-xylene or DMF at 180 °C, or the ketal from 4-phenylcyclohexanone decomposed at 140 °C
thermal decomposition of 4. At 140 °C, heating of PPG 1 under argon in 15 h, and as high as 87% of the ketal from
neat for 5 h resulted in a reaction mixture of 6, 7, 8, and 4-(4-methoxyphenyl)-2-butanone decomposed under the
unreacted 1 in a ratio of 1:0.16:0.16:0.1 (Figure 1). Typi- same conditions in 17 h. The latter observation probably
cally, xanthene 6 was the major byproduct, suggesting that explains the difficulty in preparing that particular ketal by
PPG 1 type compounds can be useful precursors for pre- the neutral thermal protocols.
paring substituted xanthenes. It should be pointed out that
The new protocol can also be utilized for acetal forma-
the amounts of the byproducts and their relative ratio tion reactions of aldehydes with other α,α-diphenylsalicyl
changed with reaction conditions such as reaction time, alcohols. For example, 5-methoxy-α,α-diphenylsalicyl
temperature, and other factors including solvent, and pres- alcohol reacted with 3-phenylpropanal (3b) in p-xylene and
Eur. J. Org. Chem. 2009, 208–211
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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209

P. Wang, Y. Wang, H. Hu, X. Liang
SHORT COMMUNICATION
1
4e: 22 mg (99%). Rf = 0.5 (petroleum ether/ethyl acetate, 5:1). H
afforded the corresponding acetal in 99% yield in just 1 h,
faster than the reaction of 3b with 1 under the same condi-
tions (i.e. 96% in 6.5 h) (Table 1, Entry 2).
NMR (CDCl3, 400 MHz, characteristic peaks): δ = 7.35–7.24 (m,
10 H), 6.39 (d, J = 2.8 Hz, 1 H), 5.95 (d, J = 2.8 Hz, 1 H), 4.92 (d,
J = 3.5 Hz, 1 H), 4.89 (d, J = 3.5 Hz, 1 H), 3.85 (s, 3 H), 3.58 (s,
3 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 152.4, 149.10, 149.09,
146.3, 144.38, 144.37, 137.24, 137.22, 129.59, 129.57, 128.1, 127.9,
127.8, 127.3, 125.71, 125.70, 104.6, 104.5, 98.94, 98.88, 96.44,
96.38, 83.99, 83.97, 56.17, 56.16, 55.5, 43.6, 43.5, 29.1, 29.0, 28.2,
Conclusions
Novel neutral methods of installing PPGs onto carbonyl
groups have been developed. They can be a useful comple-
ment to the conventional acid-catalyzed approaches, espe-
cially valuable for the protection of acid-sensitive carbonyl
compounds. The side reaction of the postulated quino-
methide intermediate to 6 can possibly lead to a simple en-
try into the synthesis of various substituted xanthene skel-
etons.
27.2, 23.2, 23.0, 21.6, 20.6, 14.2, 13.9, 11.6, 11.4 ppm. IR (neat): ν
˜
= 2956, 2932, 1600, 1492, 1467, 1447, 1279, 1233, 1200, 1156, 1088,
1057, 1027, 991 cm–1. HRMS (ESI): calcd. for C29H35O4 [M + H+]
447.2535; found 447.2532.
1
4f: 18 mg (83%). Rf = 0.37 (petroleum ether/ethyl acetate, 9:1). H
NMR (CDCl3, 300 MHz): δ = 7.44–7.18 (m, 10 H), 6.40 (d, J =
2.8 Hz, 1 H), 5.92 (d, J = 2.8 Hz, 1 H), 5.90–5.74 (m, 2 H), 5.35
(d, J = 5.2 Hz, 1 H), 3.87 (s, 3 H), 3.59 (s, 3 H), 2.07 (q, J = 6.3 Hz,
2 H), 1.43–1.23 (m, 4 H), 0.87 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 152.6, 149.0, 145.7, 143.9, 137.2, 136.6,
129.2, 128.2, 128.1, 128.0, 127.8, 127.5, 125.9, 125.5, 104.5, 98.6,
Experimental Section
94.9, 84.5, 56.0, 55.5, 31.8, 30.6, 22.3, 13.9 ppm. IR (neat): ν =
˜
2927, 1600, 1492, 1468, 1444, 1227, 1200, 1155 cm–1. HRMS (ESI):
calcd. for C28H30NaO4 [M + Na+] 453.2042; found 453.2037.
Quinone Methide Dimer 2: To a solution of PPG 1 (235 mg,
0.7 mmol) in 10 mL of toluene in an ice bath was added P2O5
(298 mg, 2.1 mmol). The reaction mixture was stirred at 0 °C for
22 h. The dark red mixture was then poured into saturated
NaHCO3 solution and extracted with ethyl acetate (30 mLϫ3).
The combined organic layers were washed with brine, dried with
Na2SO4, filtered and concentrated. Flash column chromatography
on silica gel (eluted with CH2Cl2/petroleum ether, 2:1) afforded 2
(150 mg, 68%) as a white solid. Rf = 0.3 (CH2Cl2/petroleum ether,
2:1). 1H NMR (CDCl3, 400 MHz): δ = 7.54–7.02 (br. s, 20 H), 6.33
(d, J = 2.9 Hz, 2 H), 6.07 (d, J = 2.9 Hz, 2 H), 3.62 (s, 3 H), 2.85
(s, 3 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 155.9, 155.4,
139.3, 137.2, 127.4 (br.), 107.9, 98.0, 93.6, 55.7, 55.4 ppm. IR
Thermal Reaction of 1: Salicyl alcohol 1 (34 mg, 0.1 mmol) in a
flame-dried Schlenk vessel was heated at 140 °C under argon for
1
5 h. A dark red oil was obtained. A partial H NMR spectrum of
the reaction mixture is shown in Figure 1. Yields of 6, 7, and 8 were
70%, 11%, and 11%, respectively (based on 1H NMR integration).
Several small-scale reactions under slightly different reaction condi-
tions were combined for flash column chromatography to afford 6,
7 and 8 for characterization.
6: Rf = 0.73 (petroleum ether/ethyl acetate, 5:1). 1H NMR (CDCl3,
400 MHz): δ = 7.27–7.14 (m, 7 H), 7.05 (d, 7.8 H), 6.98–6.94 (m,
1 H), 6.42 (d, J = 2.7 Hz, 1 H), 6.13 (d, J = 2.7 Hz, 1 H), 5.18 (s,
1 H), 3.93 (s, 3 H), 3.67 (s, 3 H) ppm. 13C NMR (CDCl3,
100 MHz): δ = 155.2, 150.9, 148.8, 146.3, 135.2, 129.5, 128.7, 128.1,
127.8, 126.7, 125.1, 123.9, 123.2, 116.8, 103.6, 98.8, 56.2, 55.5,
(neat): ν = 3089, 3048, 3003, 2962, 2933, 2840, 1593, 1458, 1332,
˜
1221, 1201 cm–1. HRMS (ESI): calcd. for C42H37O6 [M + H+]
637.2590; found 637.2585.
45.0 ppm. IR (neat): ν = 2360, 2342, 1624, 1483, 1456, 1244, 1206,
˜
General Procedure of Protecting Aldehydes under Neutral Condi-
tions: PPG agent 1 (0.1 mmol) and aldehyde (0.05 mmol) were
stirred at 140 °C under argon. Upon completion, the reaction mix-
ture was purified by flash column chromatography to afford the
desired acetal.
1153, 1117, 1052 cm–1. HRMS (ESI): calcd. for C21H19O3 [M +
H+] 319.1334; found 319.1328.
7: Rf = 0.67 (petroleum ether/ethyl acetate, 3:1). 1H NMR (CDCl3,
300 MHz): δ = 7.41–7.36 (m, 3 H), 7.30–7.23 (m, 5 H), 7.17 (tt, J
= 7.2, 1.6 Hz, 1 H), 7.09–7.02 (m, 1 H), 6.47 (d, J = 3.0 Hz, 1 H),
6.41 (d, J = 3.0 Hz, 1 H), 3.94 (s, 3 H), 3.67 (s, 3 H), 2.72 (s, 1 H)
ppm. 13C NMR (CDCl3, 100 MHz): δ = 155.7, 149.9, 148.8, 148.2,
134.8, 129.3, 129.1, 128.4, 128.1, 127.1, 127.0, 126.4, 123.9, 117.1,
1
4a: 24 mg (94%). Rf = 0.27 (petroleum ether/ethyl acetate, 9:1). H
NMR (CDCl3, 400 MHz): δ = 7.37–7.21 (m, 10 H), 6.40 (d, J =
2.8 Hz, 1 H), 5.93 (d, J = 2.8 Hz, 1 H), 5.13 (dd, J = 6.1, 4.5 Hz,
1 H), 3.87 (s, 3 H), 3.80–3.67 (m, 2 H), 3.59 (s, 3 H), 2.19–2.09 (m,
3 H), 0.73 (s, 9 H), –0.08 (s, 3 H), –0.09 (s, 3 H) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 152.5, 148.9, 146.0, 144.0, 136.7, 129.3,
128.1, 127.99, 127.97, 127.8, 127.4, 125.9, 104.6, 98.6, 93.3, 84.2,
101.8, 100.5, 71.1, 56.6, 56.0 ppm. IR (neat): ν = 1581, 1482, 1453,
˜
1292, 1233, 1206, 1153 cm–1. HRMS (ESI): calcd. for C21H18NaO4
[M + Na+] 357.1103; found 357.1096.
58.1, 56.0, 55.5, 37.9, 25.8, 18.1, –5.48, –5.54 ppm. IR (neat): ν =
8: Rf = 0.4 (CH2Cl2/petroleum ether/ethyl acetate, 1:8:1). 1H NMR
(CDCl3, 400 MHz): δ = 7.30–7.12 (m, 10 H), 6.40 (d, J = 2.8 Hz,
1 H), 6.05 (d, J = 2.7 Hz, 1 H), 5.91 (s, 1 H), 5.33 (s, 1 H), 3.85 (s,
3 H), 3.63 (s, 3 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 152.6,
146.8, 143.3, 137.5, 129.8, 129.3, 128.2, 126.2, 106.5, 97.0, 56.0,
˜
2955, 2929, 2856, 1602, 1492, 1471, 1447, 1406, 1360, 1338, 1281,
1233, 1201, 1156, 1094, 1058 cm–1. HRMS (ESI): calcd. for
C30H38O5Si [M] 506.2489; found 506.2487.
1
4d: 22 mg (97%). Rf = 0.4 (petroleum ether/ethyl acetate, 5:1). H
55.6, 49.8 ppm. IR (neat): ν = 3520, 3025, 2938, 2838, 1600, 1494,
˜
NMR (CDCl3, 300 MHz): δ = 7.48–7.13 (m, 13 H), 6.91–6.87 (m,
1 H), 6.44 (d, J = 2.8 Hz, 1 H), 6.00 (d, J = 2.8 Hz, 1 H), 5.88 (s,
1 H), 3.86 (s, 3 H), 3.81 (s, 3 H), 3.61 (s, 3 H) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 159.6, 152.8, 149.2, 145.6, 144.0, 138.8,
136.9, 129.4, 129.3, 128.22, 128.17, 128.13, 127.8, 127.5, 125.9,
119.0, 114.7, 112.2, 104.6, 98.9, 94.6, 85.1, 56.0, 55.5, 55.3 ppm. IR
1466, 1453, 1430, 1374, 1242, 1198, 1148, 1078, 1054 cm–1. HRMS
(ESI): calcd. for C21H21O3 [M + H+] 321.1491; found 321.1483.
Acknowledgments
(neat): ν = 2935, 1603, 1464, 1280, 1226, 1199, 1156, 1055,
This work was financially supported by the University of Alabama
˜
1027 cm–1. HRMS (ESI): calcd. for C29H26NaO5 [M + Na+] at Birmingham (UAB). We thank Dr. Michael J. Jablonsky for as-
477.1678; found 477.1676.
210
sistance in NMR spectroscopy.
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Eur. J. Org. Chem. 2009, 208–211

Photolabile Carbonyl-Protecting Groups
failed to react with 1 to produce the desired ketal, whereas
the corresponding ketone underwent clean reactions under the
same conditions, and the dimethyl ketal readily reacted with
other simple 1,3-diols to produce the corresponding 1,3-diox-
anes. b) E. V. Gromachevskaya, A. G. Sakhabutdinov, V. G.
Kul’nevich, I. S. Arustamova, R. B. Valeev, B. A. Bazhenov,
Chem. Heterocycl. Compd. 1991, 27, 502–503.
a) It is well documented that quinone methides could easily
dimerize and trimerize to form spiro compounds.[4b] But the
unambiguous structure of 2 is supported by spectroscopic data.
b) L. Jurd, J. N. Roitman, Tetrahedron 1979, 35, 1567–1574.
[1] T. W. Greene, P. G. M. Wuts, Protective groups in organic syn-
thesis, Wiley, New York, 1999.
[2] a) P. Wang, H. Hu, Y. Wang, Org. Lett. 2007, 9, 1533–5; b) P.
Wang, H. Hu, Y. Wang, Org. Lett. 2007, 9, 2831–3; c) P. Wang,
Y. Wang, H. Hu, C. Spencer, X. Liang, L. Pan, J. Org. Chem.
2008, 73, 6152–7.
[3] a) However, in view of the structure of 1, we realized that the
mechanism of 1,3-dioxane formation from 1 and carbonyl
compounds under acidic conditions could be different from
that of carbonyl compounds with other 1,3-diols.[1,3b] It is likely
that a trityl carbocation intermediate is first generated from
1 upon acid treatment. Subsequent nucleophilic attack by the
carbonyl oxygen atom led to the corresponding oxonium cat-
ion, which cyclized to the desired acetal/ketal. We observed
that the dimethyl ketal of 4-(4-methoxyphenyl)butan-2-one
[4]
[5] a) The product is a mixture of two diastereomers. Similar dia-
stereomeric products were also observed in the reaction of the
ketone with 5-methoxy-α,α-diphenylsalicyl alcohol.
Received: October 2, 2008
Published Online: November 28, 2008
Eur. J. Org. Chem. 2009, 208–211
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