Selective mesylation of vicinal diols: A systematic case study

Full text of DOI:10.1021/jo981532p

8614
J . Org. Chem. 1998, 63, 8614-8616
Ta ble 1. Selective Mesyla tion of Diol 1
Selective Mesyla tion of Vicin a l Diols:
A System a tic Ca se Stu d y
concn
(M)
MsCl
(equiv)
temp
(°C)
time % yields
(h)
entry
baseb
of 2 (3)c,d
1
2
3
4
5
6
7
0.15 Et3Ne
0.15 Et3Ne
0.1
0.06 pyridine
0.06 pyridinee
0.06 collidine
0.05 collidine
1.4
1.1
1.1
1.1
1.1
1.1
1.1
-23f0
1.25
1.5
3
48
48
48
40 (32)
29 (nd)
47 (14)
56 (11)
64 (26)
61 (12)
86 (10)
Christopher J . O’Donnell and Steven D. Burke*,†
-50
(i-Pr)2NEte
-78f0
Department of Chemistry, University of
WisconsinsMadison, 1101 University Avenue,
Madison, Wisconsin 53706-1396
5
5
23
0f7 21
Received J uly 31, 1998
a
Gen er a l P r oced u r e. To a solution of diol in CH2Cl2 were
added base and MsCl at the initial temperature indicated. The
solution was warmed to the temperature indicated for the time
indicated. The reactions were quenched with water, extracted with
CH2Cl2, washed with 2 M HCl, saturated K2CO3 (aq), and then
water. Organic extracts were dried (MgSO4), filtered, concentrated,
Selective mesylation of the primary (1°) hydroxyl group
over the secondary (2°) hydroxyl group in a 1°/2° vicinal
diol system is commonly sought (eq 1).1-11 For instance,
complete primary selectivity is critical if epoxide forma-
tion from a 1°/2° vicinal diol with retention of stereoge-
nicity at the secondary site is desired. The most common
method for this transformation employs methanesulfonyl
chloride (MsCl) and pyridine, with reported yields in the
range of 56-100% for the desired primary monomesy-
late.1-6 Triethylamine (Et3N) or Hu¨nig’s Base (i-Pr2NEt)
as replacements for pyridine also afford regioselective
hydroxyl group mesylation for some vicinal diol sub-
strates.7-11 Addition of catalytic 4-(dimethylamino)-
pyridine (DMAP) has also been used to facilitate this
transformation.6,12
b
and purified by flash chromatography on silica gel. 3 equiv of
base was used except in entry 7 where 10 equiv was used.
c Isolated yields; remainder of mass balance was starting material.
d
None of the secondary monomesylate (R1 ) H, R2 ) Ms) was
observed. e A catalytic amount (5 mol %) of DMAP was added.
procedure for the reliable 1° monomesylation of vicinal
diol 1 and similar structures, as described below.
Our synthesis of hydropyran-based macrocycles with
pendant functionality required selective primary mesy-
lation of a 1°/2° vicinal diol (1, Table 1, eq 2).13 Standard
procedures for effecting this transformation gave poor
selectivities (2/3) and unsatisfactory yields of the desired
monomesylate product 2. A systematic evaluation of
methods for this transformation has led to a modified
Resu lts a n d Discu ssion
Initial attempts to selectively mesylate the primary
hydroxyl group in diol 113 using standard procedures are
summarized in Table 1. Use of Et3N as the base with a
catalytic amount of DMAP produced a mixture of the
desired monomesylate 2 and dimesylate 3 (Table 1, entry
1).7 Lower temperatures dramatically reduced the rate
† To whom all correspondence should be addressed. Phone: (608)
262-4941. Fax: (608) 265-4534. E-mail: burke@chem.wisc.edu.
(1) Harriman, G. C. B.; Poirot, A. F.; Abushanab, E. J . Med. Chem.
1992, 35, 4180.
(2) Hoppe, D.; Hilpert, T. Tetrahedron 1987, 43, 2467.
(3) Berkowitz, D. B.; Pedersen, M. L. J . Org. Chem. 1995, 60, 5368.
(4) de March, P.; Figueredo, M.; Font, J .; Monsalvatje, M. Synth.
Commun. 1995, 25, 331.
(5) Takahata, H.; Inose, K.; Momose, T. Heterocycles 1994, 38, 269.
(6) Aristoff, P. A.; J ohnson, P. D. J . Org. Chem. 1992, 57, 6234.
(7) Crossland, R. K.; Servis, K. L. J . Org. Chem. 1970, 35, 3195.
(8) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Medici, A.; Pedrini, P.
Synthesis 1988, 9, 685.
(9) Fo¨hlisch, B.; Krimmer, D.; Gehrlach, E.; Ka¨shammer, D. Chem.
Ber. 1988, 121, 1585.
(10) J ung, M. E.; Shaw, T. J . J . Am. Chem. Soc. 1980, 102, 6304.
(11) Ando, K.; Yamada, T.; Takaishi, Y.; Shibuya, M. Heterocycles
1989, 29, 1023.
(12) Arenesulfonylimidazoles and NaH or an alkoxide base have
been used to convert 1°/2° vicinal diols to epoxides with retention at
the 2° center, suggesting selective, albeit transient, 1° arenesulfony-
lation. See: (a) Eisenberg, C.; Knochel, P. J . Org. Chem. 1994, 59, 3760.
(b) Cink, R. D.; Forsyth, C. J . J . Org. Chem. 1995, 60, 8122, and
references therein. (c) For a systematic study of selective acetylation
and, to a more limited extent, acylation, sulfonylation, and silylation
of primary versus secondary alcohols, see: Ishihara, K.; Kurihara, H.;
Yamamoto, H. J . Org. Chem. 1993, 58, 3791. This study examined only
1-octanol versus 2-octanol for selective mesylation, a competition that
differs in electronic and steric issues from the substrate studied herein.
Selectivities exceeding 9:1 for 1-octanol mesylation were observed by
Yamamoto using collidine, N,N-diisopropylethylamine (Hu¨nig’s base),
and 1,2,2,6,6-pentamethylpiperidine as bases.
of this reaction, but did give 2 selectively (Table 1, entry
2). At a slightly lower concentration, use of Hu¨nig’s base
(i-Pr2NEt, -78 °C with slow warming to 0 °C) with a
catalytic amount of DMAP provided an increase in mono/
dimesylate selectivity (3.3:1) over that in entry 1; how-
ever, the yield (47%) of the desired mesylate 2 was still
unsatisfactory (Table 1, entry 3).11 Switching to pyridine
as the base and lowering the concentration further
increased mono/dimesylate selectivity (5:1), but the yield
of the desired monomesylate 2 was still low at 56% (Table
1, entry 4).1-5 Addition of a catalytic amount of DMAP
accelerated the reaction and increased the yield of
monomesylate 2 (64%), at the expense of selectivity (2.5:
1,Table 1, entry 5).6 The mono/dimesylate selectivity
remained the same (5:1) in switching from pyridine to
collidine (2,4,6-trimethylpyridine), but the yield of the
monomesylate increased slightly to 61% (Table 1, entry
6 vs entry 4). Finally, increasing the amount of collidine
to 10 equiv and decreasing the reaction temperature
(13) Burke, S. D.; O’Donnell, C. J .; Hans, J . J .; Moon, C. W.; Ng, R.
A.; Adkins, T. W.; Packard, G. K. Tetrahedron Lett. 1997, 38, 2593.
10.1021/jo981532p CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/29/1998

Notes
J . Org. Chem., Vol. 63, No. 23, 1998 8615
Ta ble 2. Com p a r ison of Ba ses for Selective Mesyla tion .
Ch a r t 1. Oth er Exa m p les of Selective
Mon om esyla tion
% yield
% yield
entry
base
of 2b
of 3b,c
1
2
3
4
5
pyridine
2,6-lutidine
collidine
2,6-di-tert-butyl-4-methylpyridine
Et3N
47
29
84
0
8
0
8
0d
18
52
a
Reaction conditions: concentration (0.05 M), MsCl (1.1 equiv),
base (10 equiv), reaction time (15.5 h). The general procedure
detailed in Table 1, footnote a was used with the MsCl added at
b
0 °C, stirred for 1 h, and then warmed to 7 °C for 14.5 h. Isolated
yields, remainder of mass balance was recovered starting material.
c None of the monomesylate at the secondary alcohol center (R1 )
d
H, R2 ) Ms) was observed. 90% recovered starting material.
range (0 to 7 °C) increased both the selectivity (8.6:1) and
yield of monomesylate 2 to an acceptable 86% (Table 1,
entry 7).
Selectivity determinants for the mesylation reaction
merit brief review. It is known that the reaction of
methanesulfonyl chloride with Et3N results in a very
reactive sulfene intermediate,14-16 which is unlikely to
be kinetically selective, as reflected in the result in Table
1, entry 1. The increased selectivity observed when using
Hu¨nig’s base can be attributed to its lower basicity, thus
generating less of the reactive sulfene intermediate in
the reaction mixture at a given time. Upon switching to
pyridine bases, the mechanism for this reaction probably
changes, by analogy to acylation chemistry. Fersht and
J encks have shown that acylation reactions using pyri-
dine bases proceed through acylpyridinium ions as reac-
tive species.17,18 By production of these acylpyridinium
ions, pyridines act as nucleophilic catalysts, a concept
that has led to the advent of DMAP and related acylation
catalysts.19,20 Assuming that the source of mesylation
selectivity is kinetic, we believed that increasing the
steric bulk about the pyridine nitrogen would increase
selectivity. Therefore, a more detailed investigation of
the effects of substitution about the pyridine ring was
performed (Table 2, eq 3).
catalyzed by pyridine bases.20,21 Substitution with elec-
tron-donating groups (EDG) ortho to the pyridine nitro-
gen decreases the catalytic activity of the pyridinium salt,
whereas pyridines with para EDG substitution have
increased activity.21 In correspondence with the cited
acylation studies, when pyridine is replaced by 2,6-
lutidine the amount of isolated monomesylate 2 de-
creases, yet an increase in selectivity is observed, prob-
ably due to decreased reactivity of the mesyllutidinium
species formed because of increased steric bulk.21 In-
creasing substitution further by including a methyl group
para to the nitrogen in addition to the two ortho methyl
substituents, i.e., collidine, electronically increases the
activity of this nucleophilic catalyst, resulting in a higher
yield of the desired monomesylate 2 (Table 2, entry 3).
Increased selectivity compared to that of pyridine can
once again be attributed to the steric hindrance of the
methyl groups flanking the mesylcollidinium nitrogen.
Further increase of the steric bulk ortho to the pyridine
nitrogen (Table 2, entry 4) resulted in no reaction. It
should be noted that, among the substituted pyridine
nucleophiles of Table 2, DMAP was not employed due to
its 5500-fold increase in activity over pyridine as a
nucleophilic acylation catalyst,19,20 resulting in little or
no selectivity (see Table 1, entries 1-3 and 5).
In summary, the optimal conditions for the selective
primary mesylation of 1°/2° vicinal diol 1 and related
systems have been determined to be 10 equiv of collidine
and 1.1 equiv of methanesulfonyl chloride, run at a
temperature of 0-7 °C for 12-24 h and a concentration
of 0.05 M in CH2Cl2. Typical yields of desired monome-
sylate 2 from reaction of diol 1 on a gram scale are 82-
86% and have been as high as 94%. Direct use of the
resulting primary mesylate13 as an electrophilic site or
conversion to the corresponding terminal epoxide12a,b are
both accommodated by this method. These conditions
have also proven superior in our labs for selective 1°
mesylations of many structurally diverse diol and triol
The experiments in Table 2 employed the optimal
conditions for selectively mesylating diol 1 (Table 1, entry
7), varying only the base. It was observed that substitu-
tion at the positions ortho to the pyridine nitrogen
resulted in an increase in mono/dimesylate selectivity at
the expense of yield (Table 2, entry 1 vs 2); however,
additional substitution at the para position enhanced
both selectivity and yield of the desired product (Table
2, entry 1 vs entry 3). Further increase of steric bulk at
the ortho positions resulted in no reaction (Table 2, entry
4). Under these conditions, the use of Et3N resulted in
an increase in selectivity from that reported previously
(Table 2, entry 5 vs Table 1, entry 1); however, it was
still moderate (3:1) in comparison to the result with
collidine (Table 2, entry 5 vs entry 3).
The results in Table 2 can be explained by reasoning
analogous to that found in the literature on acylations
(14) Opitz, G. Angew. Chem., Int. Ed. Engl. 1967, 6, 107.
(15) Truce, W. E.; Norell, J . R. J . Am. Chem. Soc. 1963, 85, 3231.
(16) King, J . F.; Lee, T. W. S. J . Am. Chem. Soc. 1969, 91, 6524.
(17) Fersht, A. R.; J encks, W. P. J . Am. Chem. Soc. 1970, 92, 5432.
(18) Fersht, A. R.; J encks, W. P. J . Am. Chem. Soc. 1969, 91, 2125.
(19) Ho¨fle, G.; Steglich, W.; Vorbru¨ggen, H. Angew. Chem., Int. Ed.
Engl. 1978, 17, 569.
(21) Kirichenko, A. I.; Litvinenko, L. M.; Dotsenko, I. N.; Kotenko,
N. G.; Nikkel’sen, E.; Berestetskaya, V. D. Dokl. Akad. Nauk. SSSR,
Ser. Khim. 1979, 244, 1125.
(20) Scriven, E. F. V. Chem. Soc. Rev. 1983, 12, 129.

8616 J . Org. Chem., Vol. 63, No. 23, 1998
Notes
1772, 1354, 1175 cm-1; 1H NMR (CDCl3, 300 MHz) δ 5.98 (ddd,
1H, J ) 10.2, 5.8, 2.1 Hz), 5.77 (br d, 1H, J ) 10.3 Hz), 4.78
(ABq, 2H, J AB ) 12.0 Hz, ∆vAB ) 27.5 Hz), 4.43 (d, 1H, J ) 3.3
Hz), 4.40 (ap d, 2H, J ) 5.2 Hz), 4.37-4.33 (m, 1H), 3.89 (br q,
1H, J ) 5.0 Hz), 3.43 (br s, 1H), 3.05 (s, 3H), 2.64-2.57 (m, 1H),
1.00 (d, 3H, J ) 6.6 Hz); 13C NMR (CDCl3, 75 MHz) δ 168.6 (C),
131.9 (CH), 124.5 (CH), 94.4 (C), 76.1 (CH), 75.4 (CH), 74.2
(CH2), 71.6 (CH), 70.6 (CH2), 37.4 (CH3), 31.5 (CH), 14.9 (CH3);
MS (FAB) m/e (relative intensity, assignment) 433.0 (65, M +
substrates (Chart 1). These representative cases all
proceeded with excellent regioselectivities in the isolated
yields shown parenthetically.
Exp er im en ta l Section
Gen er a l. Dichloromethane (CH2Cl2), triethylamine (Et3N),
diisopropylethylamine (i-Pr2NEt), pyridine, and 2,6-lutidine were
distilled from calcium hydride prior to use. 4-(Dimethylamino)-
pyridine (DMAP) was recrystallized from toluene. Methane-
sulfonyl chloride was distilled under reduced pressure prior to
use. 2,6-Di-tert-butyl-4-methylpyridine was purchased from
Aldrich22 and was used without further purification. All reac-
tions were performed in flame-dried glassware under a stream
of nitrogen. Silica gel chromatography was performed according
to the method of Still.23 Proton nuclear magnetic resonance (1H
NMR) spectra were recorded at 300 MHz. Chemical shifts are
reported in parts per million (ppm, δ) relative to Me4Si (δ 0.00),
and coupling constants (J ) are reported in hertz (Hz). Carbon-
13 nuclear magnetic resonance (13C NMR) spectra were recorded
at 75 MHz. Where indicated, distortionless enhancement by
polarization transfer (DEPT) was used to assign carbon reso-
nances as CH3, CH2, CH, or C. Chemical shifts are reported in
ppm relative to Me4Si (δ, 0.00). Elemental analyses were
performed by Desert Analytics Laboratories (Phoenix, AZ).
P r ep a r a tion of (2R,3S,6S)-6-[(1R)-1-Hyd r oxy-2-m eth yl-
su lfon yleth yl]-3-m eth yl-3,6-d ih yd r o-2H-p yr a n -2-ca r boxy-
lic Acid 2,2,2-Tr ich lor oeth yl Ester (2). To a solution of diol
113 (4.32 g, 12.95 mmol) in CH2Cl2 (260 mL) was added collidine
(17.1 mL, 129.5 mmol) at ambient temperature. The solution
was cooled to 0 °C, and 13.9 mL (14.25 mmol) of 1.03 M MsCl
(in CH2Cl2) was added. After stirring for 2 h at 0 °C, the solution
was placed in a refrigerator (7 °C) for 18 h without stirring. The
reaction was quenched with water (100 mL), the phases were
separated, and the aqueous layer was extracted with CH2Cl2 (3
× 50 mL). The combined organic extracts were washed with
5% HCl (aq) (50 mL), dried (MgSO4), filtered, and concentrated
in vacuo. Purification by flash chromatography on silica gel
(elution with 1:1 EtOAc/hexanes) afforded 4.44 g (10.83 mmol,
84%) of the monomesylate 2 as a colorless oil and 509 mg (1.04
mmol, 8.0%) of the dimesylate 3.
Na+), 411.0 (100, M + H+); isotope pattern calculated for C12
17O7Cl3S + Na+ matches that observed. Anal. Calcd for C12
H17O7Cl3S: C, 35.01; H, 4.16. Found: C, 35.24; H, 4.49.
-
-
H
Da ta for d im esyla te 3: Rf 0.45 (50% EtOAc in hexanes);
[R]22 +60.3 (c ) 0.58, CH2Cl2); IR (thin film) 1774, 1358, 1176
D
cm-1; 1H NMR (CDCl3, 300 MHz) δ 6.08 (ddd, 1H, J ) 10.3, 5.5,
2.2 Hz), 5.76 (ddd, 1H, J ) 10.3, 1.5, 1.5 Hz), 4.83 (ap q, 1H, J
) 4.8 Hz), 4.78 (ABq, 2H, J AB ) 11.8 Hz, ∆vAB ) 14.1 Hz), 4.56-
4.52 (m, 1H), 4.53 (d, 2H, J ) 4.8 Hz), 4.46 (d, 1H, J ) 3.3 Hz),
3.15 (s, 3H), 3.07 (s, 3H), 2.65-2.60 (m, 1H), 1.02 (d, 3H, J )
7.0 Hz); 13C NMR (CDCl3, 75 MHz) δ 167.8 (C), 133.3 (CH), 122.7
(CH), 94.4 (C), 79.0 (CH), 75.6 (CH), 74.2 (CH2), 74.0 (CH), 67.1
(CH2), 38.9 (CH3), 37.7 (CH3), 31.3 (CH), 14.9 (CH3); MS (FAB)
m/e (relative intensity, assignment) 513 (100, M + Na+); isotope
pattern calculated for C13H19O9S2Cl3 + Na+ matches that
observed.
Ack n ow led gm en t. This research was supported by
NIH Grant GM 28321 (S.D.B.) and NIH Chemisty/
Biology Interface Training Grant GM08505 (C.J .O.).
Additional support from Merck and Pfizer is gratefully
acknowledged. Lei J iang, J eannie Phillips, Brian Aus-
tad, J eremy Hans, J ennifer Pace, J onathan Young, and
Choong Woon Moon graciously supplied the data for
compounds 4-9. The University of Wisconsin NMR
facility receives financial support from NSF (CHE-
9208463) and NIH (1S10 RR0 8389-D1).
Su p p or tin g In for m a tion Ava ila ble: Copies of NMR
spectra of 2 and 3 and of other vicinal diol monomesylates 4-9
prepared as described above (14 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
Da ta for m on om esyla te 2: Rf 0.26 (50% EtOAc in hexanes);
[R]22 +78.9 (c ) 1.24, CH2Cl2); IR (thin film) 3600-3200 (br),
D
(22) Aldrich Chemical Co., 1001 West Saint Paul Ave., Milwaukee,
WI 53233.
(23) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.
J O981532P