α-Hydroxylation of carbonyls using iodine

Article abstract of DOI:10.1016/j.tetlet.2004.11.092

The α-hydroxylation of ketones and aldehydes to α-hydroxyketals mediated by iodine under basic conditions in MeOH is described. Enolates generated under the reaction conditions are iodinated and the resulting α-iodocarbonyl is transformed into the hydroxyketal. The use of iodine for this chemistry represents an economical and practical alternative to existing methods for this transformation.

Full text of DOI:10.1016/j.tetlet.2004.11.092

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 447–450
a-Hydroxylation of carbonyls using iodine
Michael J. Zacuto* and Dongwei Cai
Department of Process Research, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA
Received 27 October 2004; revised 15 November 2004; accepted 16 November 2004
Available online 2 December 2004
Abstract—The a-hydroxylation of ketones and aldehydes to a-hydroxyketals mediated by iodine under basic conditions in MeOH is
described. Enolates generated under the reaction conditions are iodinated and the resulting a-iodocarbonyl is transformed into the
hydroxyketal. The use of iodine for this chemistry represents an economical and practical alternative to existing methods for this
transformation.
Ó 2004 Elsevier Ltd. All rights reserved.
a-Hydroxy carbonyls are versatile synthetic intermedi-
ates that are useful for the preparation of 1,2-amino-
alcohols,1 a-aminocarbonyls,2 and 1, 2-diols.3 In
addition to their utility as synthetic precursors, a-hydr-
oxy carbonyls are important substructures present in a
wide variety of natural products and pharmaceutically
important compounds.4 Consequently, this motif has
attracted considerable attention from the synthetic com-
munity. A powerful method for their preparation from
the parent carbonyl involves the hydroxylation of pre-
formed enolates or enol ethers with a variety of oxidiz-
ing agents, including peroxyacids,5 OsO4,6 MoOPh,7
oxaziridines,8 and DMDO.9 Recently a number of
reports have described the proline-catalyzed asymmetric
a-oxyamination of ketones and aldehydes using nitroso-
benzene as the oxidant.10 An alternative approach
involves the one step formation of a-hydroxyketals from
the corresponding carbonyl via the hydroxylation of
enolates formed in situ. This strategy largely involves
the use of hypervalent iodine reagents such as iodoso-
benzene, (diacetoxy)iodobenzene, and o-iodosylbenzoic
acid.11 These reactions proceed via an intermediate
epoxide, and bear mechanistic similarity to the tradi-
tional method of treating preformed a-halo ketones with
alkoxides (Scheme 1).12
O
MeO
R
O
OH
I
I
MeO-
O
Ar
MeO-/MeOH
O
R
R
Ar
MeOH
R'
R'
R'
MeO OMe
OH
MeO-
MeOH
R
R'
Scheme 1.
accomplish the same one step transformation (Scheme
2).
While the a-hydroxylation of ketones using electro-
chemically generated halogens is known,2a,13 we are
unaware of any efforts that utilize elemental iodine as
a reagent for this reaction. Furthermore, the impracti-
cality of conducting electrochemistry on a multi-kilo-
gram scale warranted an investigation of the use of I2.
One advantage of such a process would be the elimina-
tion of iodobenzene as a by-product, which can be diffi-
cult to remove from a non-crystalline product without
resorting to column chromatography. Another advan-
tage would be the dramatically reduced cost of the
oxidizing reagent, which is particularly pronounced on
scale. Lastly, any potential safety hazards associated
We recently required a practical synthesis of an a-hydr-
oxy ketal and were intrigued by the possibility of finding
a surrogate for the established hypervalent iodine re-
agents. In particular, we wondered whether I2 could
O
O
MeO-, I2
MeOH
MeO OMe
OH
MeO-
I
R
R
R
MeOH
Keywords: a-Hydroxylation; Iodine; Acyloins.
R'
R'
R'
*
Corresponding author. Tel.: +1 732 5940363; fax: +1 732 5945170;
e-mail: michael_zacuto@merck.com
Scheme 2.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.11.092

448
M. J. Zacuto, D. Cai / Tetrahedron Letters 46 (2005) 447–450
Table 1. a-Hydroxylation of cyclic ketones
5). Entry 6 reflects the enolate equilibrium under the
reaction conditions, and highlights the ability to form
tertiary alcohols using this process. Acyclic ketones did
not react to afford the corresponding a-hydroxyketals.
Instead, esters resulting from a Favorskii rearrangement
were obtained.
Entry
Ketone
Product
Isolated
yield (%)
MeO OMe
O
OH
1
89
85
81
50
O
1
O
O
Entry 1 (Table 1) demonstrates the benefits of using I2
and thus avoiding the production of organic by-prod-
ucts. Upon completion of the I2 addition, the reaction
was stirred for 1 h at room temperature. Following the
removal of MeOH and the addition of toluene, the inor-
ganic KI was removed by filtration, and the filtrate was
concentrated to afford pure 1.
MeO OMe
OH
2
3
4
2
MeO OMe
O
OH
S
3
S
MeO OMe
Attempts to extend this reaction to conjugated 6-mem-
bered ring ketones were unsuccessful due to the pro-
pensity of the intermediate a-iodoketone to undergo
elimination. For example, subjection of chromanone
to the conditions established for the synthesis of 1 led
to a complex mixture of products, of which chromone
was the major product isolated in 48% yield (Eq. 1).
Likewise, a-tetralone led to a complex mixture, of
which 1-napthol was the major product isolated in
33% yield (Eq. 2). Subjection of 2-iodotetralone12 to
the reaction conditions led to an identical reaction
profile.
O
OH
N
N
Bn
Bn
4
MeO OMe
O
OH
5
6
80
75
N
Boc
N
Boc
5
MeO OMe
MeO OMe
Me OH
O
OH
Me
Me
+
6
(2:1)
7
O
O
All reactions performed by addition of a 0.6 M solution of I2/MeOH
over 1.5 h to a 0.5 M solution of ketone in MeOH containing 2.4 equiv
of KOH (0–5 °C).
KOH, I2
MeOH
48%
+ decomposition
products
O
O
ð1Þ
with iodoso compounds would be avoided.14 We report
herein the successful employment of I2 for the a-hydroxy-
lation of aldehydes and ketones, including the scope and
limitations of this reaction.
48%
O
OH
KOH, I2
MeOH
33%
+ decomposition
products
Our studies began with the investigation of ketones in
the proposed a-hydroxylation reaction. Addition of
1.0 equiv of solid I2 in one portion to a room tempera-
ture solution of tetrahydro-4H-pyran-4-one in MeOH
with 2.0 equiv of KOH led to the formation of the de-
sired a-hydroxyketal 1 in 53% yield. The use of Br2 in-
stead of I2 failed to afford any trace of 1. After
experimenting with a variety of reaction conditions, we
discovered that a controlled addition of a MeOH solu-
tion of I2 to the KOH/MeOH solution containing the
ketone led to higher yields. Furthermore, cooling
the reaction temperature led to improved efficiency of
the reaction. The optimized conditions involved the
addition of an I2/MeOH solution (1.1 equiv of I2) over
1.5–2 h to a 0–5 °C solution containing 2.4 equiv of
KOH, MeOH, and the ketone, affording 1 in 89% yield.
These conditions were applied to a series of 6-membered
ring cyclic ketones and the results are summarized in
Table 1.15
ð2Þ
The ring size of the cyclic ketone had a dramatic effect
on the efficiency of the a-hydroxylation. For example,
cyclopentanone reacted to form an intermediate a,a-di-
iodoketone, giving rise to a complex mixture including
2,2-dimethoxycyclopentanone as the major product
(Eq. 3).16 The reactivity of cycloheptanone demon-
strated that 7-membered rings follow both mono- and
diiodination pathways. Reaction of 1.1 equiv of I2 with
cycloheptanone gave rise to a 2.2:1 mixture of the de-
sired a-hydroxyketal 8 and methyl-1-cyclohexene-1-car-
boxylate (9),16 the latter likely resulting from a Favorskii
rearrangement of an initially formed a,a-diiodoketone
followed by elimination (Eq. 4).17 Variation of the rate
of I2 addition did not affect this ratio.
Tetrahydropyranone, tetrahydrothiopyranone, and pip-
eridone heterocycles are well tolerated, as well as a Boc-
protected amine. We speculate that the presence of a
basic amine is likely responsible for the lower yield of
4 (Table 1, entry 4) relative to that of 5 (Table 1, entry
O
O
O
I
OMe
OMe
KOH, I2
MeOH
I
ð3Þ

M. J. Zacuto, D. Cai / Tetrahedron Letters 46 (2005) 447–450
449
Table 2. a-Hydroxylation of aldehydes
Entry
Aldehyde
Product
Temp (°C)
ꢀ10
Time (h)a
1
Isolated yield (%)
OMe
OMe
1
72
CHO
Ph
Ph
Ph
OH
11
OMe
Ph
2
3
CHO
ꢀ10
1
50
75
OMe
OH
12
OMe
OMe
Me
CH3(CH2)7CHO
0
0.5
5
OH
13
14
OMe
CHO
HO
4
5
rt
rt
0.5
0.5
77
80
OMe
OMe
CHO
BocN
HO
OMe
BocN
15
a Time of I2 addition.
1986, 73–77; (b) Tsuchihashi, G.; Maniwa, K.; Iiuchijama,
S. J. Am. Chem. Soc. 1974, 96, 4280–4283.
3. For an excellent review concerning the diastereo-selective
synthesis of 1,2-diols from nucleophilic addition to a-
hydroxyketone derivatives, see: Mengel, A.; Reiser, O.
Chem. Rev. 1999, 99, 1191–1223.
O
MeO OMe
CO2Me
KOH, I2
OH
ð4Þ
+
MeOH
8
9
(19%)
(43%)
4. See Moriarty, R. M.; Berglund, B. A.; Penmasta, R.
Tetrahedron Lett. 1992, 33, 6065–6068, and references
cited therein.
5. (a) Rubottom, G. M.; Vazquez, M. A.; Pelegrina, D. R.
Tetrahedron Lett. 1974, 15, 4319–4322; (b) Brook, A. G.;
Macrae, D. M. J. Organomet. Chem. 1974, 77, C19–C21;
(c) Hassner, A.; Reuss, R. H.; Pinnick, H. W. J. Org.
Chem. 1975, 40, 3427–3429; Rubottom, G. M.; Gruber,
J. M. J. Org. Chem. 1978, 43, 1599–1602.
6. (a) McCormick, J. P.; Tomasik, W.; Johnson, M. W.
Tetrahedron Lett. 1981, 22, 607–610; (b) Toyosjima, K.;
Okuyama, T.; Fueno, T. J. Org. Chem. 1980, 45, 1600–
1604; (c) Morikawa, K.; Park, J.; Anderson, P. G.;
Hashiyama, T.; Sharpless, K. B. J. Am. Chem. Soc.
1993, 115, 8463.
We next turned our attention towards the a-hydroxy-
lation of aldehydes (Table 2).18 Variations in the struc-
ture of the aldehyde required minor adjustments of the
reaction parameters in order to obtain optimal yields.
The lower yield of 12 (Table 2, entry 2) reflects the insta-
bility of phenylacetaldehyde towards basic conditions,
evidenced by the observation of various aldehyde poly-
1
merization products by H NMR. Entry 5 is significant
in that the 4-piperidinol substructure is an important
pharmaceutical moiety,19 and thus 15 may serve as a
valuable synthetic building block.
7. Vedejs, E.; Engler, D. A.; Telschow, J. E. J. Org. Chem.
1978, 43, 188–196.
8. (a) Davis, F. A.; Chen, B. C. Chem. Rev. 1992, 92, 919–
934; (b) Davis, F. A.; Sheppard, A. C. Tetrahedron 1992,
45, 5703–5742.
In summary, we have described the iodine-mediated a-
hydroxylation of cyclic 6-membered ring ketones and
aldehydes to a-hydroxyketals in good yield. The de-
scribed process offers advantages over existing methods
for the synthesis of these valuable compounds in terms
of practicality, cost, and waste. This process also pro-
vides superior yields of a-hydroxyketals relative to the
use of hypervalent iodine reagents or of electrochemical
conditions. Studies aimed at further definition of the
scope of this hydroxylation chemistry are underway
and will be reported in due course.
9. Guertin, K. R.; Chan, T. H. Tetrahedron Lett. 1991, 32,
715–718.
10. Aldehyde a-hydroxylation: (a) Zhong, G. Angew. Chem.
2003, 115, 4379–4382; Angew. Chem., Int. Ed. 2003, 42,
4247–4250; (b) Brown, S. P.; Brochu, M. P.; Sinz, C. J.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125, 10808–
10809; (c) Hayashi, Y.; Yamaguchi, J.; Hibino, K.; Shoji,
M. Tetrahedron Lett. 2003, 44, 8293–8296; Ketone a-
´
´
hydroxylation: (d) Bøgevig, A.; Sunden, H.; Cordova, A.
Angew. Chem. 2004, 116, 1129–1132; Angew. Chem., Int.
Ed. 2004, 43, 1109–1112; (e) Hayashi, Y.; Yamaguchi, J.;
Sumiya, T.; Shoji, M. Angew. Chem. 2004, 116, 1132–
1135; Angew. Chem., Int. Ed. 2004, 43, 1112–1115. The
initially formed adducts can be converted to the corre-
sponding a-hydroxy carbonyl.
References and notes
1. For example, see: Ghosh, A. K.; McKee, S. P.; Sanders,
W. M. Tetrahedron Lett. 1991, 32, 711–714.
2. (a) Shono, T.; Matsamura; Shono, T.; Matsamura, Y.;
Inoue, K.; Iwasaki, F. J. Chem. Soc., Perkins Trans. 1
11. (a) Moriarty, R. M. Tetrahedron Lett. 1981, 22, 1283–
1286; (b) Moriarty, R. M.; John, L. S.; Du, P. C. J. Chem.

450
M. J. Zacuto, D. Cai / Tetrahedron Letters 46 (2005) 447–450
Soc., Chem. Commun. 1981, 641–664; (c) Moriarty, R. M.;
1H), 3.99–3.91 (m, 1H), 3.80–3.73 (m, 1H), 3.29 (s, 3H),
3.28 (s, 3H), 3.22–3.10 (br m, 1H), 2.95–2.80 (br m, 1H),
1.91–1.77 (m, 2H), 1.50 (s, 9 H); 13C NMR (CD3OD,
400 MHz) d 158.0, 100.5, 81.0, 67.7, 48.3, 47.9, 42.0, 41.0,
28.8, 28.2; Anal. Calcd for C12H23O5N: C, 55.16; H, 8.87;
N, 5.36. Found: C, 55.14; H, 9.01; N, 5.31. For charac-
terization of 1: Ref. 2a For characterization of 2, 6 and 7
see Ref. 10e and citations therein.
Hu, H. Tetrahedron Lett. 1981, 22, 2747–2750; (d)
Moriarty, R. M.; Gupta, S. C.; Hu, H.; Berenschot, D.
R.; White, K. B. J. Am. Chem. Soc. 1981, 103, 686–688; (e)
Moriarty, R. M.; Hou, K. C. Tetrahedron Lett. 1984, 25,
691–694; (f) Moriarty, R. M.; Prakash, O.; Karalis, P.;
Prakash, I. Tetrahedron Lett. 1984, 25, 4745–4748; (g)
Moriarty, R. M.; Berglund, B. A.; Penmasta, R. Tetra-
hedron Lett. 1992, 33, 6065–6068.
16. Various products resulting from further reaction of 2,2-
dimethoxycyclopentanone were also observed (1H NMR).
A similar product distribution was observed in Refs. 13a
and 13b.
12. Stevens, C. L.; Beereboom, J. J.; Rutherford, K. G. J. Am.
Chem. Soc. 1955, 77, 4590–4593, and references cited
therein.
13. (a) Barba, F.; Elinson, M. N.; Escudero, J.; Feducovich, S.
K. Tetrahedron Lett. 1996, 37, 5759–5762; (b) Barba, F.;
Elinson, M. N.; Escudero, J.; Feducovich, S. K. Tetrahe-
dron 1997, 53, 4427–4436.
14. Hypervalent iodine reagents iodosobenzene and O-iodo-
sobenzoic acid carry explosion hazards. For example, See
(a) Gert, V. Chem. Eng. News 1989, 30, 2; (b) Katritzky,
A. R.; Savage, G. P.; Gauos, J. K.; Durst, H. D. Org.
Proc. and Proc. Int. 1989, 21, 157–162. (Diacetoxy)-
iodobenzene is converted to iodosobenzene under the
reaction conditions employed in Ref. 11.
17. Subjection of methyl cyclohexanecarboxylate to the reac-
tion conditions did not result in the formation of 9 but
instead returned unreacted ester. For further discussion
see Refs. 14a and 14b. For related reactions see: (a)
Mookherjee, B. D.; Trenkle, R. W.; Patel, R. J. Org.
Chem. 1971, 36, 3266–3270; (b) Krabbenhoft, H. O. J.
Org. Chem. 1979, 44, 4285–4294.
18. General experimental procedure for the synthesis of 11–
15: To a solution of 24.0 mmol KOH (1.6 g of A.C.S.
reagent pellets, 85% KOH assay) in 21 mL of anhydrous
MeOH (at the specified temperature) was added the
aldehyde (10.0 mmol) over several minutes. Following a
5–10 min age, a solution of I2 (2.8 g, 11.0 mmol) in
18.5 mL of MeOH was added over the specified time
(Table 2). Upon completion of the addition, the solution
was gradually warmed to room temperature and aged for
an additional hour. The resulting solution was then
concentrated, and 50 mL of PhMe was added and the
resulting slurry was filtered. Concentration afforded the
crude a-hydroxyacetal, which was suitable for further use,
but could be purified by silica gel chromatography. Data
15. General experimental procedure for the synthesis of 1–7:
To a 0–5 °C solution of 24.0 mmol KOH (1.6 g of A.C.S.
reagent pellets, 85% KOH assay) in 21 mL of anhydrous
MeOH was added the ketone (10.0 mmol) over several
minutes. Following a 5–10 min age, a solution of I2 (2.8 g,
11.0 mmol) in 18.5 mL of MeOH was added over 1.5 h.
Upon completion of the addition, the solution was
gradually warmed to room temperature and aged for an
additional hour. The resulting solution was then concen-
trated, and 50 mL of PhMe was added and the resulting
slurry was filtered. Concentration afforded the crude a-
hydroxyketal, which was suitable for further use, but
could be purified by silica gel chromatography. Data for 3:
1H NMR (CD3OD, 400 MHz) d 3.94 (dd, J1 = 2.1 Hz,
J2 = 4.8 Hz, 1H), 3.29 (s, 3H), 3.25 (s, 3H), 3.11 94 (dd,
J1 = 2.0 Hz, J2 = 13.8 Hz, 1H), 2.76–2.69 (m, 1H), 2.64–
2.58 (m, 1H), 2.44–2.38 (m, 1H), 2.05–2.01 (m, 2H); 13C
NMR (CD3OD, 400 MHz) d 100.5, 67.1, 48.2, 47.6, 33.9,
30.6, 25.7; Anal. Calcd for C7H14O3S: C, 47.17; H, 7.92; S,
1
for 15: H NMR (CDCl3, 400 MHz) d 3.93 (s, 1H), 3.93–
3.86 (br m, 2H), 3.53 (s, 6H), 3.10–3.01 (m, 2H), 1.57–1.47
(m, 2H), 1.53–1.42 (m, 2H), 1.44 (s, 9H); 13C NMR
(CDCl3, 400 MHz) d 154.8, 110.5, 79.2, 72.0, 58.1, 39.1,
31.5, 28.4. Anal. Calcd for C13H25O5NÆ1/3 H2O: C, 55.50;
H, 9.20; N, 4.98. Found C, 55.71; H, 8.95; N, 4.92. For
characterization of 11, see Ref. 2a. For characterization of
12, see: Yamamoto, H.; Tsuda, M.; Sakaguchi, S.; Ishii, Y.
J. Org. Chem. 1997, 62, 7174–7177; , For characterization
of 13, see: Yoshida, J.; Matsanuga, S.; Murata, T.; Isoe, S.
Tetrahedron 1991, 47, 615–624; , For characterization of
14, see:Boni, M.; Forti, L.; Ghelfi, F.; Pagoni, U. M.
Tetrahedron 1994, 50, 7897–7902.
1
17.99. Found C, 46.91; H, 7.84; S, 17.69. Data for 4: H
NMR (CD3OD, 400 MHz) d 7.41–7.28 (m, 5H), 3.73–3.71
(m, 1H), 3.59 (d, J = 12.9 Hz, 1H), 3.52 (d, J = 12.9 Hz,
1H), 3.27 (s, 3H), 3.25 (s, 3H), 2.79–2.72 (m, 1H), 2.67–
2.60 (m, 1H), 2.49–2.45 (m, 1H), 2.27–2.19 (m, 1H), 1.99–
1.91 (m, 1H), 1.82–1.77 (m, 1H); 13C NMR (CD3OD,
400 MHz) d 139.1, 130.7, 129.4, 128.4, 100.4, 69.0, 63.5,
57.6, 50.8, 48.5, 48.1, 28.9; Anal. Calcd for C14H21O3N: C,
66.91; H, 8.42; N, 5.57. Found C, 66.95; H, 8.43; N, 5.53.
Data for 5: 1H NMR (CD3OD, 400 MHz) d 4.06–4.00 (m,
19. For a recent example, see: Hale, J. J.; Budhu, R. J.; Mills,
S. G.; MacCoss, M.; Gould, S. L.; DeMartino, J. A.;
Springer, M. S.; Siciliano, S. J.; Malkowitz, L.; Schleif, W.
A.; Hazuda, D.; Miller, M.; Kessler, J.; Danzeisen, R.;
Holmes, K.; Lineberger, J.; Carella, A.; Carver, G.; Emini,
E. A. Bioorg. Med. Chem. Lett. 2002, 20, 2997–3000.