Tin-free radical addition of acyloxymethyl to imines

Article abstract of DOI:10.1021/ol8014978

(Chemical Equation Presented) Acyloxymethyl radicals were generated from the corresponding iodomethyl esters and successfully underwent addition to the C=N bond of N-Ts, N-PMP, and N-Dpp imines by the action of dimethylzinc or triethylborane. Ethyl acetate, toluene, and benzene as well as dichloromethane were suitable solvents. The utility of acyloxymethyl radicals as a hydroxymethyl anion equivalent was highlighted by the facile hydrolysis of the acyloxy moiety of the adducts to give the corresponding amino alcohol derivatives in good to high yield.

Full text of DOI:10.1021/ol8014978

ORGANIC
LETTERS
2008
Vol. 10, No. 17
3805-3808
Tin-Free Radical Addition of
Acyloxymethyl to Imines
Ken-ichi Yamada, Mayu Nakano, Masaru Maekawa, Tito Akindele, and
Kiyoshi Tomioka*
Graduate School of Pharmaceutical Sciences, Kyoto UniVersity, Yoshida, Sakyo-ku,
Kyoto 606-8501, Japan
tomioka@pharm.kyoto-u.ac.jp
Received July 2, 2008
ABSTRACT
Acyloxymethyl radicals were generated from the corresponding iodomethyl esters and successfully underwent addition to the CdN bond of
N-Ts, N-PMP, and N-Dpp imines by the action of dimethylzinc or triethylborane. Ethyl acetate, toluene, and benzene as well as dichloromethane
were suitable solvents. The utility of acyloxymethyl radicals as a hydroxymethyl anion equivalent was highlighted by the facile hydrolysis of
the acyloxy moiety of the adducts to give the corresponding amino alcohol derivatives in good to high yield.
Synthetically useful transformations that are otherwise dif-
ficult to accomplish have been achieved through reactions
involving radical species.1 In addition, these reactions are
usually carried out under mild conditions. An R-oxygenated
alkyl radical is classified as a stabilized nucleophilic radical
and is accordingly an R-oxygenated carbanion equivalent,
while the anion counterpart, R-alkoxycarbanion, is a rela-
tively unstable species. Examples of the most successful
methods to generate R-oxygenated carbanion are tin-lithium
exchange of (1-alkoxyalkyl)tin compounds2 and iodine-
magnesium exchange of iodomethyl carboxylates.3 Usually,
strictly anhydrous and deoxygenated atmosphere, strongly
basic conditions, and also low temperature are required for
this type of carbanion chemistry. In contrast, R-alkoxy and
R-hydroxyalkyl radicals have been generated via C-H bond
cleavage under milder conditions and utilized in C-C bond
forming reactions as nucleophilic R-oxygenated carbon
units.4 The major problem of this strategy was, however,
the requirement of a large amount (usually 20-250 equiv)
of the corresponding ether or alcohol as a radical source.
The generation of this class of radical via C-heteroatom
bond cleavage using a tin compound has been utilized in
sugar chemistry as well as in a number of total syntheses.5
Although R-oxygenated C-centered radicals were efficiently
generated from the radical sources in these examples, the
use of organotinhydrides is a critical drawback, especially
from an ecological point of view, because of difficulty in
complete removal and toxicity of tin compounds.6 Moreover,
the radical source, R-halogenated ether is rather unstable and
easily hydrolyzed under ordinary atmosphere. R-Acyloxy-
alkyl radical is also expected to react as a nucleophilic
R-oxygenated carbon unit. The corresponding radical source,
R-halogenated alkyl benzoate and pivalate are so stable
(4) (a) Fraser-Reid, B.; Anderson, R. C.; Hicks, D. R.; Walker, D. L.
Can. J. Chem. 1977, 55, 3986–3995. (b) Fontana, F.; Minisci, F.; Yan,
Y. M.; Zhao, L. Tetrahedron Lett. 1993, 34, 2517–2520. (c) Gong, J.; Fuchs,
P. L. J. Am. Chem. Soc. 1996, 118, 4486–4487. (d) Peleta, O.; C´ırkva, V.;
Buskova´, Z.; Bo¨hm, S. J. Fluorine Chem. 1997, 86, 155–171. (e) Kim, S.;
Kim, N.; Chung, W.-J.; Cho, C. H. Synlett 2001, 937–940. (f) Torrente, S.;
Alonso, R. Org. Lett. 2001, 3, 1985–1987. (g) Jang, Y.-J.; Shih, Y.-K.;
Liu, J.-Y.; Kuo, W.-Y.; Yao, C.-F. Chem. Eur. J. 2003, 9, 2123–2128. (h)
Ferna´ndez, M.; Alonso, R. Org. Lett. 2003, 5, 2461–2464. (i) Ferna´ndez,
M.; Alonso, R. Org. Lett. 2005, 7, 11–14. (j) Oka, R.; Nakayama, M.;
Sakaguchi, S.; Ishii, Y. Chem. Lett. 2006, 35, 1104–1105. (k) Geraghty,
N. W. A.; Lally, A. Chem. Commun. 2006, 4300–4302.
(1) (a) Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.;
Wiley-VCH: Weinheim, 2001; Vols. 1 and 2. (b) Radicals in Synthesis I &
II; Gansa¨uer, A., Ed.; Topics in Current Chemistry 263 and 264; Springer-
Verlag: Berlin, Heidelberg, 2006.
(5) (a) Lee, E. In Radicals in Organic Synthesis; Renaud, P., Sibi, M. P.,
Eds.; Wiley-VCH: Weinheim, 2001; Vol. 2, pp 303-333. (b) Buckmelter,
A. J.; Rychnovsky, S. D. In Radicals in Organic Synthesis; Renaud, P.,
Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001; Vol. 2, pp 334-349.
(6) Review: Neumann, W. P. Synthesis 1987, 665–683.
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1822.
10.1021/ol8014978 CCC: $40.75
Published on Web 07/31/2008
2008 American Chemical Society

toward hydrolysis7 that the purification by silica gel column
chromatography is possible. However, the synthetic utility
of R-acyloxyalkyl radical has scarcely been studied. Besides,
reported examples are limited to addition to an intramolecular
CdC bond,8,9 with the exception of one example of
intermolecular addition of propanoyloxymethyl radical,
generated from iodomethyl propanoate using an organotin
reagent.10,11
for another 6 h at room temperature to give adduct 3a in
66% yield (Scheme 1).
Scheme 1
We have studied the dimethylzinc-air-initiated direct
generation of R-alkoxyalkyl radicals from ethers through
hydrogen abstraction and their reactions for the functional-
ization of ethers.12 We also succeeded in the tin-free
generation of primary alkyl radicals from the corresponding
alkyl iodides via dimethylzinc-air-radical process.13-15
Herein, we report the tin-free generation of acyloxymethyl
radicals from the corresponding iodomethyl esters and their
reaction with imines to show their utility as hydroxymethyl
anion equivalents.
First, we examined the reaction of iodomethyl pivalate
(1a)16 with N-tosylbenzaldimine (2a). To a solution of 1a
(3 mmol) and 2a (1 mmol) in dichloromethane (1 mL) was
added a 1.0 M solution of dimethylzinc in hexane (1 mL, 1
mmol). The mixture was stirred at room temperature under
ordinary atmosphere, while a solution of dimethylzinc (1 mL,
1 mmol) was added every 2 h. After addition of a total
amount of 5 mmol of dimethylzinc, the mixture was stirred
The reaction using diethylzinc, in place of dimethylzinc,
failed to give the expected product 3a but instead the ethyl
adduct in 78% yield along with the reduced product,
N-benzyltoluenesulfonamide, in 9% yield. When a hexane
solution of triethylborane17 was used instead of dimethylzinc,
the reaction proceeded more cleanly to give 3a in 96% yield
after 20 h (Table 1, entry 1). The ester functionality of 1
Table 1. Addition of Acyloxymethyl Radicals, Generated from
1, to Imines 2 Mediated by Et3B-Aira
(7) Ulich, L. H.; Adams, R. J. Am. Chem. Soc. 1921, 43, 660–667.
(8) Beckwith, A. L. J.; Pigou, P. E. J. Chem. Soc., Chem. Commun.
1986, 85–86
(9) Meyer, C.; Marek, I.; Courtemanche, G.; Normant, J.-F. Tetrahedron
1994, 50, 11665–11692
(10) Degueil-Castaing, M.; Navarro, C.; Ramon, F.; Maillard, B. Aust.
.
Et3B time 3/yield
entry 1/R1
2
R2
R3
(equiv) (h)
(%)
.
1
2
3
4
1a/t-Bu 2a Ph
1b/Ph 2a Ph
1a/t-Bu 2b Ph
1b/Ph 2b Ph
4-tolSO2
4-tolSO2
4-MeOC6H4
4-MeOC6H4
Ph2PO
9
5
20 3a/96
14 3b/79
J. Chem. 1995, 48, 233–240
.
(11) Recently, intermolecular addition of phthalimidylmethyl radical to
electron-rich CdC bond has been reported: Quiclet-Sire, B.; Zard, S. Z.
5
5
7
8
3c/89
3d/84
Org. Lett. 2008, 10, 3279–3282
.
(12) (a) Yamada, K.; Fujihara, H.; Yamamoto, Y.; Miwa, Y.; Taga, T.;
Tomioka, K. Org. Lett. 2002, 4, 3509–3511. (b) Yamada, K.; Yamamoto,
Y.; Tomioka, K. Org. Lett. 2003, 5, 1797–1799. (c) Yamada, K.; Yamamoto,
Y.; Maekawa, M.; Tomioka, K. J. Org. Chem. 2004, 64, 1531–1534. (d)
Yamamoto, Y.; Yamada, K.; Tomioka, K. Tetrahedron Lett. 2004, 45, 795–
797. (e) Yamamoto, Y.; Maekawa, M.; Akindele, T.; Yamada, K.; Tomioka,
K. Tetrahedron 2005, 61, 379–384. (f) Akindele, T.; Yamamoto, Y.;
Maekawa, M.; Umeki, H.; Yamada, K.; Tomioka, K. Org. Lett. 2006, 8,
5729–5732. (g) Yamada, K.; Umeki, H.; Maekawa, M.; Yamamoto, Y.;
Akindele, T.; Nakano, M.; Tomioka, K. Tetrahedron 2008, 64, 7258–7265.
(h) Review: (i) Yamada, K.; Yamamoto, Y.; Tomioka, K. J. Synth. Org.
Chem. Jpn. 2004, 62, 1158–1165.
5b 1a/t-Bu 2c Ph
20
8
18
9
48 3e/80
20 3f/88
48 3g/82
22 3h/94
24 3i/67
6
7
1a/t-Bu 2d 4-ClC6H4
4-tolSO2
1a/t-Buc 2e 4-MeC6H4 4-tolSO2
8d 1a/t-Bu 2f 4-MeOC6H4 4-tolSO2
9
1a/t-Bu 2g Ph(CH2)2
4-tolSO2
8
a 1 (3 equiv) and Et3B (3 equiv) were initially added, and the rest of
Et3B was portionwise added (1 equiv/2 h). b Toluene was used as a solvent
in place of CH2Cl2. BF3·OEt2 (total 6 equiv) was added in four portions.
c 9 equiv. d BF3·OEt2 (total 3 equiv) was added in three portions.
(13) Yamada, K.; Yamamoto, Y.; Maekawa, M.; Akindele, T.; Umeki,
H.; Tomioka, K. Org. Lett. 2006, 8, 87–89
.
(14) Studies on reactions of dialkylzinc and molecular oxygen: (a)
Lewinski, J.; Marciniak, W.; Lipkowski, J.; Justyniak, I. J. Am. Chem. Soc.
2003, 125, 12698–12699. (b) Lewinski, J.; Sliwinski, W.; Dranka, M.;
Justyniak, I.; Lipkowski, J. Angew. Chem., Int. Ed. 2006, 45, 4826–4829.
(c) Jana, S.; Berger, R. J. F.; Fro¨hlich, R.; Pape, T.; Mitzel, N. W. Inorg.
and 3 was inert under these conditions. It is worthy of note
that the reaction can be conducted at room temperature under
ordinary atmosphere. In contrast, the reaction of methoxym-
ethyl radical, generated from methyl iodomethyl ether with
dimethylzinc-air, required -78 °C to give the methoxym-
ethylated analogue of 3a in 95% yield, and the reaction at
room temperature resulted in a complex mixture including
no desired adduct.18
Chem. 2007, 46, 4293–4297
(15) For dialkylzinc-mediated radical reactions, see: Bazin, S.; Feray,
L.; Bertrand, M. P. Chimia 2006, 60, 260–265, and references cited therein
.
.
(16) Prepared from the corresponding commercially available chloride
according to the reported procedure: Knochel, P.; Chou, T.; Jubert, C.;
Rajagopal, D. J. Org. Chem. 1993, 58, 588–599
.
(17) Reviews: (a) Olliver, C.; Renaud, P. Chem. ReV. 2001, 101, 3415–
3434. (b) Yorimitsu, H.; Oshima, K. In Radicals in Organic Synthesis;
Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001; Vol. 1, pp
11-27.
Iodomethyl benzoate (1b)19 was also a good radical
precursor to give benzoyloxymethylated adduct 3b20 in 79%
(18) The other reactions of methoxymethyl radical, generated from
methyl iodomethyl ether, were also conducted at -78 °C: (a) Halland, N.;
Jørgensen, A. J. Chem. Soc., Perkin Trans. 1 2001, 1290–1295. (b) Bazin,
S.; Feray, L.; Vanthuyne, N.; Bertrand, M. P. Tetrahedron 2007, 63, 77–
(19) Prepared from the corresponding commercially available chloride
according to the reported procedure: Wittig, G.; Jautelat, M. Liebigs Ann.
Chem. 1967, 702, 24–37.
85.
(20) Sun, X.; Ye, S.; Wu, J. Eur. J. Org. Chem. 2006, 21, 4787–4790.
3806
Org. Lett., Vol. 10, No. 17, 2008

yield after 14 h under similar conditions (entry 2). The
reaction proceeded smoothly with N-(4-methoxyphenyl)
(PMP) imine 2b, and products 3c and 3d were obtained in
89% and 84% yields after 7 and 8 h, respectively (entries 3
and 4). Interestingly, the reactions of N-PMP imines were
faster than those with more electron-deficient N-tosyl imines.
The reaction of N-diphenylphosphinoyl (Dpp) imine 2c also
proceeded in toluene by using 20 equiv of triethylborane to
give 3e in 80% yield in the presence of trifluoroborane
diethyl etherate (entry 5). In the absence of trifluoroborane
diethyl etherate, the reaction produced 3e in only 20% yield
and 2c was recovered in 40% yield after 48 h using 20 equiv
of triethylborane. The products were also obtained in good
yields in the reaction of N-tosyl imines 2d and 2e derived
from 4-chloro and 4-methylbenzaldehyde (entries 6 and 7),
although the latter required 9 equiv of 1a and prolonged
reaction time.
Scheme 3
The presence of trifluoroborane also facilitated the reaction
of electron-rich 4-methoxybenzaldehyde imine 2f. In the
presence of trifluoroborane diethyl etherate (3 equiv), adduct
3h was obtained in 94% yield after 22 h (entry 8). In the
absence of trifluoroborane diethyl etherate, 3h was obtained
in only 41% yield along with recovered 2f in 45% yield after
60 h using 9 equiv of 1a and 20 equiv of triethylborane
(Scheme 2). Catalytic amounts (0.2 equiv) of other additives,
resulting in quantitative recovery of the starting aldehyde.
This result encouraged us to perform a three-component
reaction. To a mixture of 1a (3 equiv), benzaldehyde, and
p-anisidine (1 equiv) was added triethylborane (10 equiv in
eight portions). Addition of pivaloyloxymethyl radical
exclusively took place to imine 2b, generated in situ, to give
adduct 3c in 65% yield after 22 h (Scheme 4). No addition
product to the CdO bond of benzaldehyde was detected.
Scheme 2
Scheme 4
Demasking of the alcohol moiety of pivalate and benzoate
product 3 was readily achieved by basic hydrolysis with
potassium hydroxide in aqueous methanol at room temper-
ature to give the corresponding amino alcohols 421 in good
to high yield (Scheme 5).
copper(II) triflate and scandium triflate also promoted the
reaction to give 3h in 72% and 65% yields after 22 and 7 h,
respectively, using 9 equiv of triethylborane. On the contrary,
bismuth triflate and indium triflate failed to facilitate the
reaction to give 3h in 36% and <1% yields, respectively,
after 25 h. As shown in entry 9, the reaction is also applicable
to aliphatic imine 2g derived from hydrocinnamaldehyde to
give 3i in 67% yield.
Scheme 5
Dichloromethane was replaceable with toluene, benzene,
or environmentally acceptable ethyl acetate, as shown in
Scheme 3. The products were obtained in good to high yield
comparable to the corresponding reaction in dichloromethane.
It is noteworthy that ethyl acetate, which is usually incom-
patible with a carbanion, was usable in these radical
conditions. This wide choice of solvents is one of the
advantages of this reaction.
In summary, we have developed the reaction of acyloxym-
ethyl radicals, generated from the corresponding iodomethyl
(21) 4a: (a) Gandon, L. A.; Russell, A. G.; Gu¨veli, T.; Brodwolf, A. E.;
Kariuki, B. M.; Spencer, N.; Snaith, J. S. J. Org. Chem. 2006, 71, 5198–
5207. 4b: (b) Govindarajan, S.; Kari, V.; Babu, V. Tetrahedron Lett. 2004,
45, 8253–8256.
The reaction of benzaldehyde with 1a (3 equiv) and
triethylborane (5 equiv in three portions) failed to proceed,
Org. Lett., Vol. 10, No. 17, 2008
3807

esters, with a variety of imines. The utility of acyloxymethyl
radicals as hydroxymethyl anion equivalents was highlighted
by the easy demasking of the alcohol moiety in standard
basic conditions. It is advantageous that the reaction can be
conducted without tin reagents under ordinary atmosphere
at room temperature with a choice of ecological solvents.
Furthermore, the radical precursor, iodomethyl ester, is rather
stable and easy to handle.
ence”, a Grant-in-Aid for Young Scientists (B), a Grant-in-
Aid for Scientific Research in Priority Areas “Advanced
Molecular Transformations of Carbon Resources”, a Grant-
in-Aid for Scientific Research (A), and the Targeted Proteins
Research Program of the Ministry of Education, Culture,
Sports, Science, and Technology, Japan.
Supporting Information Available: Experimental pro-
cedures and characterization data of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. This research was partially supported
by the 21st Century COE (Center of Excellence) Program
“Knowledge Information Infrastructure for Genome Sci-
OL8014978
3808
Org. Lett., Vol. 10, No. 17, 2008